Feasibility and acceptance of electronic quality of life assessment in general practice: an implementation study

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Resistance to the CCR5 Inhibitor 5P12-RANTES Requires a Difficult Evolution from CCR5 to CXCR4 Coreceptor Use

Viral resistance to small molecule allosteric inhibitors of CCR5 is well documented, and involves either selection of preexisting CXCR4-using HIV-1 variants or envelope sequence evolution to use inhibitor-bound CCR5 for entry. Resistance to macromolecular CCR5 inhibitors has been more difficult to demonstrate, although selection of CXCR4-using variants might be expected. We have compared the in vitro selection of HIV-1 CC1/85 variants resistant to either the small molecule inhibitor maraviroc (MVC) or the macromolecular inhibitor 5P12-RANTES. High level resistance to MVC was conferred by the same envelope mutations as previously reported after 16–18 weeks of selection by increasing levels of MVC. The MVC-resistant mutants were fully sensitive to inhibition by 5P12-RANTES. By contrast, only transient and low level resistance to 5P12-RANTES was achieved in three sequential selection experiments, and each resulted in a subsequent collapse of virus replication. A fourth round of selection by 5P12-RANTES led, after 36 weeks, to a “resistant” variant that had switched from CCR5 to CXCR4 as a coreceptor. Envelope sequences diverged by 3.8% during selection of the 5P12-RANTES resistant, CXCR4-using variants, with unique and critical substitutions in the V3 region. A subset of viruses recovered from control cultures after 44 weeks of passage in the absence of inhibitors also evolved to use CXCR4, although with fewer and different envelope mutations. Control cultures contained both viruses that evolved to use CXCR4 by deleting four amino acids in V3, and others that maintained entry via CCR5. These results suggest that coreceptor switching may be the only route to resistance for compounds like 5P12-RANTES. This pathway requires more mutations and encounters more fitness obstacles than development of resistance to MVC, confirming the clinical observations that resistance to small molecule CCR5 inhibitors very rarely involves coreceptor switching

Is Chest X-ray an Adequate Screening Tool for the Diagnosis of Blunt Thoracic Aortic Injury?

Rationale The MARAN (Macular Relocation in Age-related Neovascular disease) trial was planned to assess the effectiveness of full macular relocation (MR) in patients with neovascular age-related macular degeneration (AMD). Design Randomised, prospective, controlled clinical trial. Methods Patients suffering from visual loss because of AMD were randomised to either surgery or a control group receiving standard treatment (observation or photodynamic therapy (PDT)). The primary end point was the change of visual acuity (VA) (ETDRS) 52 weeks after randomisation compared with initial VA, and secondary end points included reading performance, contrast sensitivity, stability of fixation, eye-specific quality of life, and the absolute number of letters read correctly at 52 weeks compared with initial examination. Results Owing to early determination, only 28 patients were included in the study. The study did not show a difference between the two groups with respect to the final visual result or any of the secondary outcomes measured. The study was limited by the low recruitment that was, at least in part, attributed to the inherent risks for those patients randomised to the surgical arm of the study as well as to the emerging new treatments for AMD. Conclusion The results of the MARAN trial failed to recruit a sufficient number of patients and a superiority of surgery over observation or PDT in patients with exudative AMD was not shown. There was a trend that the reading function was superior after surgery. In the light of the new pharmacological treatments, surgical options such as MR will be an option for only selected cases. © 2010 Macmillan Publishers Limited All rights reserved.link_to_subscribed_fulltex