In vitro and ex vivo testing of tenofovir shows it is effective as an HIV-1 microbicide

Background: Tenofovir gel has entered into clinical trials for use as a topical microbicide to prevent HIV-1 infection but has no published data regarding pre-clinical testing using in vitro and ex vivo models. To validate our findings with on-going clinical trial results, we evaluated topical tenofovir gel for safety and efficacy. We also modeled systemic application of tenofovir for efficacy. Methods and Findings: Formulation assessment of tenofovir gel included osmolality, viscosity, in vitro release, and permeability testing. Safety was evaluated by measuring the effect on the viability of vaginal flora, PBMCs, epithelial cells, and ectocervical and colorectal explant tissues. For efficacy testing, PBMCs were cultured with tenofovir or vehicle control gels and HIV-1 representing subtypes A, B, and C. Additionally, polarized ectocervical and colorectal explant cultures were treated apically with either gel. Tenofovir was added basolaterally to simulate systemic application. All tissues were challenged with HIV-1 applied apically. Infection was assessed by measuring p24 by ELISA on collected supernatants and immunohisto-chemistry for ectocervical explants. Formulation testing showed the tenofovir and vehicle control gels were >10 times isosmolar. Permeability through ectocervical tissue was variable but in all cases the receptor compartment drug concentration reached levels that inhibit HIV-1 infection in vitro. The gels were non-toxic toward vaginal flora, PBMCs, or epithelial cells. A transient reduction in epithelial monolayer integrity and epithelial fracture for ectocervical and colorectal explants was noted and likely due to the hyperosmolar nature of the formulation. Tenofovir gel prevented HIV-1 infection of PBMCs regardless of HIV-1 subtype. Topical and systemic tenofovir were effective at preventing HIV-1 infection of explant cultures. Conclusions: These studies provide a mechanism for pre-clinical prediction of safety and efficacy of formulated microbicides. Tenofovir was effective against HIV-1 infection in our algorithm. These data support the use of tenofovir for pre-exposure prophylaxis. © 2010 Rohan et al

Demography and disorders of German Shepherd Dogs under primary veterinarycare in the UK

The German Shepherd Dog (GSD) has been widely used for a variety of working roles. However, concerns for the health and welfare of the GSD have been widely aired and there is evidence that breed numbers are now in decline in the UK. Accurate demographic and disorder data could assist with breeding and clinical prioritisation. The VetCompassTM Programme collects clinical data on dogs under primary veterinary care in the UK. This study included all VetCompassTM dogs under veterinary care during 2013. Demographic, mortality and clinical diagnosis data on GSDs were extracted and reported

Prevalence of Disorders Recorded in Dogs Attending Primary-Care Veterinary Practices in England

Purebred dog health is thought to be compromised by an increasing occurence of inherited diseases but inadequate prevalence data on common disorders have hampered efforts to prioritise health reforms. Analysis of primary veterinary practice clinical data has been proposed for reliable estimation of disorder prevalence in dogs. Electronic patient record (EPR) data were collected on 148,741 dogs attending 93 clinics across central and south-eastern England. Analysis in detail of a random sample of EPRs relating to 3,884 dogs from 89 clinics identified the most frequently recorded disorders as otitis externa (prevalence 10.2%, 95% CI: 9.1-11.3), periodontal disease (9.3%, 95% CI: 8.3-10.3) and anal sac impaction (7.1%, 95% CI: 6.1-8.1). Using syndromic classification, the most prevalent body location affected was the head-and-neck (32.8%, 95% CI: 30.7-34.9), the most prevalent organ system affected was the integument (36.3%, 95% CI: 33.9-38.6) and the most prevalent pathophysiologic process diagnosed was inflammation (32.1%, 95% CI: 29.8-34.3). Among the twenty most-frequently recorded disorders, purebred dogs had a significantly higher prevalence compared with crossbreds for three: otitis externa (P = 0.001), obesity (P = 0.006) and skin mass lesion (P = 0.033), and popular breeds differed significantly from each other in their prevalence for five: periodontal disease (P = 0.002), overgrown nails (P = 0.004), degenerative joint disease (P = 0.005), obesity (P = 0.001) and lipoma (P = 0.003). These results fill a crucial data gap in disorder prevalence information and assist with disorder prioritisation. The results suggest that, for maximal impact, breeding reforms should target commonly-diagnosed complex disorders that are amenable to genetic improvement and should place special focus on at-risk breeds. Future studies evaluating disorder severity and duration will augment the usefulness of the disorder prevalence information reported herein

Multi-stakeholder consensus on a target product profile for an HIV cure

Developing a cure for HIV is a global priority. Target product profiles are a tool commonly used throughout the drug development process to align interested parties around a clear set of goals or requirements for a potential product. Three distinct therapeutic modalities (combination therapies, ex-vivo gene therapy, and in-vivo gene therapy) for a target product profile for an HIV cure were identified. Using a process of expert face-to-face consultation and an online Delphi consultation, we found a high degree of agreement regarding the criteria for the optimum target product profile. Although the minimum attributes for a cure were debated, the broad consensus was that an acceptable cure need not be as safe and effective as optimally delivered antiretroviral therapy. An intervention that successfully cured a reasonable fraction of adults would be sufficient to advance to the clinic. These target product profiles will require further discussion and ongoing revisions as the field matures

Optimization of facade design based on the impact of interior obstructions to daylighting

Overcrowding in the perimeter zone is an inevitable issue in residential rooms with limited space. Obstructions, such as furniture and household items, may block the existing windows, and therefore affect interior daylight conditions. A facade design approach is needed that simultaneously takes into account daylighting and the volume of usable space for obstructions in the perimeter zone of such rooms. This study simulates daylight distributions in a typical small residential room with obstructions in front of windows. The simulation consists of two parts. First, the effects on horizontal illuminances caused by different positions and shapes of obstructions are examined under an overcast sky. Second, the maximum usable space volumes for obstructions of 51 optimized facade configurations are calculated in terms of four window-to-wall ratios (WWRs). The results of this study show that optimizing the forms of facade design can increase the usable interior space volume and meet the daylighting requirements of Chinese standards for small residential rooms. Additionally, by using the optimized facade forms, a facade with a WWR value of 50% provides the maximum usable space for obstructions. Based on the above results, this paper presents two matrices that can help architects in selecting the appropriate fenestration methods and confirming the size of usable space and allocation for residents

Extreme sensitivity in Snowball Earth formation to mountains on PaleoProterozoic supercontinents

During the PaleoProterozoic 2.45 to 2.2 billion years ago, several glaciations may have produced Snowball Earths. These glacial cycles occurred during large environmental change when atmospheric oxygen was increasing, a supercontinent was assembled from numerous landmasses, and collisions between these landmasses formed mountain ranges. Despite uncertainties in the composition of the atmosphere and reconstruction of the landmasses, paleoclimate model simulations can test the sensitivity of the climate to producing a Snowball Earth. Here we present a series of simulations that vary the atmospheric methane concentration and latitudes of west–east-oriented mountain ranges on an idealised supercontinent. For a given methane concentration, the latitudes of mountains control whether a Snowball Earth forms or not. Significantly, mountains in middle latitudes inhibited Snowball Earth formation, and mountains in low latitudes promoted Snowball Earth formation, with the supercontinent with mountains at ±30° being most conducive to forming a Snowball Earth because of reduced albedo at low latitudes. We propose that the extreme sensitivity of a Snowball Earth to reconstructions of the paleogeography and paleoatmospheric composition may explain the observed glaciations, demonstrating the importance of high-quality reconstructions to improved understanding of this early period in Earth’s history