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

Complications of syndesmotic screw removal

Background: Currently, the metallic syndesmotic screw is the gold standard in the treatment of syndesmotic disruption. Whether or not this screw needs to be removed remains debatable. The aim of the current study was to determine the complications which occur following routine removal of the syndesmotic screw following operative treatment of unstable ankle fractures. Methods: This was a retrospective study with consecutive cases in a Level-2 Trauma center. All patients with routine removal of a syndesmotic screw, following the treatment of an unstable ankle fracture, between January 1, 2004 and November 30, 2010 were included. Complications recorded were: 1) minor or major wound infection following removal of the syndesmotic screw, 2) recurrent syndesmotic diastasis, and 3) unnecessary removal of a broken screw, not recognized during preoperative planning prior to surgery. Results: A total of 76 patients were included. A wound infection occurred in 9.2% (N=7) of which 2.6% (N=2) were deep infections requiring reoperation. Recurrent syndesmotic diastasis was found in 6.6% (N=5) of patients, and in 6.6% (N=5) screws were broken at the time of implant removal. In the group with recurrent diastasis the screws were removed significantly earlier compared with the group without recurrent diastasis (Mann- Whitney U-test; p = 0.011) and the group with screw breakage had their screws significantly longer in place compared with the group without breakage (p = 0.038). Conclusion: A total of 22.4% complications occurred upon routine removal of the syndesmotic screw. Removal might therefore be considered only in selected c

Emotions and Digital Well-being. The rationalistic bias of social media design in online deliberations

In this chapter we argue that emotions are mediated in an incomplete way in online social media because of the heavy reliance on textual messages which fosters a rationalistic bias and an inclination towards less nuanced emotional expressions. This incompleteness can happen either by obscuring emotions, showing less than the original intensity, misinterpreting emotions, or eliciting emotions without feedback and context. Online interactions and deliberations tend to contribute rather than overcome stalemates and informational bubbles, partially due to prevalence of anti-social emotions. It is tempting to see emotions as being the cause of the problem of online verbal aggression and bullying. However, we argue that social media are actually designed in a predominantly rationalistic way, because of the reliance on text-based communication, thereby filtering out social emotions and leaving space for easily expressed antisocial emotions. Based on research on emotions that sees these as key ingredients to moral interaction and deliberation, as well as on research on text-based versus non-verbal communication, we propose a richer understanding of emotions, requiring different designs of online deliberation platforms. We propose that such designs should move from text-centred designs and should find ways to incorporate the complete expression of the full range of human emotions so that these can play a constructive role in online deliberations

Reappraising myocardial fibrosis in severe aortic stenosis: an invasive and non-invasive study in 133 patients

Aims: To investigate myocardial fibrosis (MF) in a large series of severe aortic stenosis (AS) patients using invasive biopsy and non-invasive imaging. Methods and results: One hundred thirty-three patients with severe, symptomatic AS accepted for surgical aortic valve replacement underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) and extracellular volume fraction (ECV) quantification. Intra-operative left ventricular (LV) biopsies were performed by needle or scalpel, yielding tissue with (n = 53) and without endocardium (n = 80), and compared with 10 controls. Myocardial fibrosis occurred in three patterns: (i) thickened endocardium with a fibrotic layer; (ii) microscopic scars, with a subendomyocardial predominance; and (iii) diffuse interstitial fibrosis. Collagen volume fraction (CVF) was elevated (P < 0.001) compared with controls, and higher (P < 0.001) in endocardium-containing samples with a decreasing CVF gradient from the subendocardium (P = 0.001). Late gadolinium enhancement correlated with CVF (P < 0.001) but not ECV. Both LGE and ECV correlated independently (P < 0.001) with N-terminal pro-brain natriuretic peptide and high-sensitivity-troponin T. High ECV was also associated with worse LV remodelling, left ventricular ejection fraction and functional capacity. Combining high ECV and LGE better identified patients with more adverse LV remodelling, blood biomarkers and histological parameters, and worse functional capacity than each parameter alone. Conclusion: Myocardial fibrosis in severe AS is complex, but three main patterns exist: endocardial fibrosis, microscars (mainly in the subendomyocardium), and diffuse interstitial fibrosis. Neither histological CVF nor the CMR parameters ECV and LGE capture fibrosis in its totality. A combined, multi-parametric approach with ECV and LGE allows best stratification of AS patients according to the response of the myocardial collagen matrix

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

Evaluation of non-chemical seed treatment methods for the control of Alternaria dauci and A. radicina on carrot seeds

The current study was initiated to evaluate the efficacy of physical methods (hot water, aerated steam, electron treatment) and agents of natural origin (resistance inducers, plant derived products, micro-organisms) as seed treatments of carrots for control of Alternaria dauci and A. radicina. Control of both Alternaria species by seed treatment with the resistance inducers was generally poor. Results were also not satisfactory with most of the formulated commercial micro-organism preparations. Based on the average of five field trials, one of these, BA 2552 (Pseudomonas chlororaphis), provided a low but significant increase in plant stand. Among the experimental micro-organisms, the best results were obtained with Pseudomonas sp. strain MF 416 and Clonostachys rosea strain IK726. A similar level of efficacy was provided by seed treatment with an emulsion (1%) of thyme oil in water. Good and consistent control was generally achieved with the physical methods aerated steam, hot water and electron treatment. Aerated steam treatment was, apart from the thiram-containing chemical standard, the best single treatment, and its performance may at least partially be due to extensive pre-testing, resulting in dosages optimally adapted to the respective seed lot. In some of the experiments the effect of the hot water treatment, which was tested at a fixed, not specifically adapted dosage, was significantly improved when combined with a Pseudomonas sp. MF 416 or C. rosea IK726 treatment. The results are discussed in relation to the outcome of experiments in which the same seed treatment methods and agents were tested in other seed-borne vegetable pathosystems

Atmospheric emissions from the deepwater Horizon spill constrain air-water partitioning, hydrocarbon fate, and leak rate

The fate of deepwater releases of gas and oil mixtures is initially determined by solubility and volatility of individual hydrocarbon species; these attributes determine partitioning between air and water. Quantifying this partitioning is necessary to constrain simulations of gas and oil transport, to predict marine bioavailability of different fractions of the gas-oil mixture, and to develop a comprehensive picture of the fate of leaked hydrocarbons in the marine environment. Analysis of airborne atmospheric data shows massive amounts (∼258,000 kg/day) of hydrocarbons evaporating promptly from the Deepwater Horizon spill; these data collected during two research flights constrain air-water partitioning, thus bioavailability and fate, of the leaked fluid. This analysis quantifies the fraction of surfacing hydrocarbons that dissolves in the water column (∼33% by mass), the fraction that does not dissolve, and the fraction that evaporates promptly after surfacing (∼14% by mass). We do not quantify the leaked fraction lacking a surface expression; therefore, calculation of atmospheric mass fluxes provides a lower limit to the total hydrocarbon leak rate of 32,600 to 47,700 barrels of fluid per day, depending on reservoir fluid composition information. This study demonstrates a new approach for rapid-response airborne assessment of future oil spills. Copyright 2011 by the American Geophysical Union

A broad distribution of the alternative oxidase in microsporidian parasites

Microsporidia are a group of obligate intracellular parasitic eukaryotes that were considered to be amitochondriate until the recent discovery of highly reduced mitochondrial organelles called mitosomes. Analysis of the complete genome of Encephalitozoon cuniculi revealed a highly reduced set of proteins in the organelle, mostly related to the assembly of ironsulphur clusters. Oxidative phosphorylation and the Krebs cycle proteins were absent, in keeping with the notion that the microsporidia and their mitosomes are anaerobic, as is the case for other mitosome bearing eukaryotes, such as Giardia. Here we provide evidence opening the possibility that mitosomes in a number of microsporidian lineages are not completely anaerobic. Specifically, we have identified and characterized a gene encoding the alternative oxidase (AOX), a typically mitochondrial terminal oxidase in eukaryotes, in the genomes of several distantly related microsporidian species, even though this gene is absent from the complete genome of E. cuniculi. In order to confirm that these genes encode functional proteins, AOX genes from both A. locustae and T. hominis were over-expressed in E. coli and AOX activity measured spectrophotometrically using ubiquinol-1 (UQ-1) as substrate. Both A. locustae and T. hominis AOX proteins reduced UQ-1 in a cyanide and antimycin-resistant manner that was sensitive to ascofuranone, a potent inhibitor of the trypanosomal AOX. The physiological role of AOX microsporidia may be to reoxidise reducing equivalents produced by glycolysis, in a manner comparable to that observed in trypanosome