Population-Level Benefits from Providing Effective HIV Prevention Means to Pregnant Women in High Prevalence Settings

Background:HIV prevalence among pregnant women in Southern Africa is extremely high. Epidemiological studies suggest that pregnancy increases the risk of HIV sexual acquisition and that HIV infections acquired during pregnancy carry higher risk of mother-to-child transmission (MTCT). We analyze the potential benefits from extending the availability of effective microbicide to pregnant women (in addition to non-pregnant women) in a wide-scale intervention.Methods and Findings:A transmission dynamic model was designed to assess the impact of microbicide use in high HIV prevalence settings and to estimate proportions of new HIV infections, infections acquired during pregnancy, and MTCT prevented over 10 years. Our analysis suggests that consistent use of microbicide with 70% efficacy by 60% of non-pregnant women may prevent approximately 40% and 15% of new infections in women and men respectively over 10 years, assuming no additional increase in HIV risk to either partner during pregnancy (RRHIV/preg = 1). It may also prevent 8-15% MTCT depending on the increase in MTCT risk when HIV is acquired during pregnancy compared to before pregnancy (RRMTCT/preg). Extending the microbicides use during pregnancy may improve the effectiveness of the intervention by 10% (RRHIV/preg = 1) to 25% (RRHIV/preg = 2) and reduce the number of HIV infections acquired during pregnancy by 40% to 70% in different scenarios. It may add between 6% (RRHIV/preg = 1, RRMTCT/preg = 1) and 25% (RRHIV/preg = 2, RRMTCT/preg = 4) to the reduction in the residual MTCT.Conclusion:Providing safe and effective microbicide to pregnant women in the context of wide-scale interventions would be desirable as it would increase the effectiveness of the intervention and significantly reduce the number of HIV infections acquired during pregnancy. The projected benefits from covering pregnant women by the HIV prevention programs is more substantial in communities in which the sexual risk during pregnancy is elevated. © 2013 Dimitrov et al

Why Can't Rodents Vomit? A Comparative Behavioral, Anatomical, and Physiological Study

The vomiting (emetic) reflex is documented in numerous mammalian species, including primates and carnivores, yet laboratory rats and mice appear to lack this response. It is unclear whether these rodents do not vomit because of anatomical constraints (e.g., a relatively long abdominal esophagus) or lack of key neural circuits. Moreover, it is unknown whether laboratory rodents are representative of Rodentia with regards to this reflex. Here we conducted behavioral testing of members of all three major groups of Rodentia; mouse-related (rat, mouse, vole, beaver), Ctenohystrica (guinea pig, nutria), and squirrel-related (mountain beaver) species. Prototypical emetic agents, apomorphine (sc), veratrine (sc), and copper sulfate (ig), failed to produce either retching or vomiting in these species (although other behavioral effects, e.g., locomotion, were noted). These rodents also had anatomical constraints, which could limit the efficiency of vomiting should it be attempted, including reduced muscularity of the diaphragm and stomach geometry that is not well structured for moving contents towards the esophagus compared to species that can vomit (cat, ferret, and musk shrew). Lastly, an in situ brainstem preparation was used to make sensitive measures of mouth, esophagus, and shoulder muscular movements, and phrenic nerve activity-key features of emetic episodes. Laboratory mice and rats failed to display any of the common coordinated actions of these indices after typical emetic stimulation (resiniferatoxin and vagal afferent stimulation) compared to musk shrews. Overall the results suggest that the inability to vomit is a general property of Rodentia and that an absent brainstem neurological component is the most likely cause. The implications of these findings for the utility of rodents as models in the area of emesis research are discussed. © 2013 Horn et al

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

Prioritization strategies in clinical practice guidelines development: a pilot study

Objective: Few methodological studies address the prioritization of clinical topics for the development of Clinical Practice Guidelines (CPGs). The aim of this study was to validate a methodology for Priority Determination of Topics (PDT) of CPGs. Methods and results: Firstly, we developed an instrument for PDT with 41 criteria that were grouped under 10 domains, based on a comprehensive systematic search. Secondly, we performed a survey of stakeholders involved in CPGs development, and end users of guidelines, using the instrument. Thirdly, a pilot testing of the PDT procedure was performed in order to choose 10 guideline topics among 34 proposed projects; using a multicriteria analysis approach, we validated a mechanism that followed five stages: determination of the composition of groups, item/domain scoring, weights determination, quality of the information used to support judgments, and finally, topic selection. Participants first scored the importance of each domain, after which four different weighting procedures were calculated (including the survey results). The process of weighting was determined by correlating the data between them. We also reported the quality of evidence used for PDT. Finally, we provided a qualitative analysis of the process. The main domains used to support judgement, having higher quality scores and weightings, were feasibility, disease burden, implementation and information needs. Other important domains suc

A Compendium of Potential Biomarkers of Pancreatic Cancer

Akhilesh Pandey and colleagues describe a compendium of potential biomarkers that can be systematically validated by the pancreatic cancer community

Phase II trial of the regulatory T cell-depleting agent, denileukin diftitox, in patients with unresectable stage IV melanoma

<p>Abstract</p> <p>Background</p> <p>We previously found that administration of an interleukin 2/diphtheria toxin conjugate (DAB/IL2; Denileukin Diftitox; ONTAK) to stage IV melanoma patients depleted CD4⁺CD25^HIFoxp3⁺regulatory T cells and expanded melanoma-specific CD8⁺T cells. The goal of this study was to assess the clinical efficacy of DAB/IL2 in an expanded cohort of stage IV melanoma patients.</p> <p>Methods</p> <p>In a single-center, phase II trial, DAB/IL2 (12 μg/kg; 4 daily doses; 21 day cycles) was administered to 60 unresectable stage IV melanoma patients and response rates were assessed using a combination of 2-[¹⁸F]-fluoro-2-deoxy-glucose (FDG)-positron emission tomography (PET) and computed tomography (CT) imaging.</p> <p>Results</p> <p>After DAB/IL2 administration, 16.7% of the 60 patients had partial responses, 5% stable disease and 15% mixed responses. Importantly, 45.5% of the chemo/immuno-naïve sub-population (11/60 patients) experienced partial responses. One year survival was markedly higher in partial responders (80 ± 11.9%) relative to patients with progressive disease (23.7 ± 6.5%; <it>p </it>value < 0.001) and 40 ± 6.2% of the total DAB/IL2-treated population were alive at 1 year.</p> <p>Conclusions</p> <p>These data support the development of multi-center, randomized trials of DAB/IL2 as a monotherapy and in combination with other immunotherapeutic agents for the treatment of stage IV melanoma.</p> <p>Trial registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT00299689">NCT00299689</a></p

Entry mode deviation: a behavioral approach to internalization theory

We explore when and why decision makers choose international entry modes (e.g., hierarchies or markets) that deviate from internalization theory’s predictions. By applying a cognitive perspective on entry mode decision making, we propose that the performance of prior international activities influences decision makers’ behavior in different ways than assumed in internalization theory. More specifically, due to a representativeness bias, underperforming (overperforming) past ventures influence the decision to change (continue using) the previous entry mode choice, which may result in an entry mode deviation. In addition, the propensity to deviate from theoretical predictions is stronger when the experience is recent and/or salient due to an availability bias. In conclusion, we argue that internalization theory can benefit from incorporating more systematically important behavioral assumptions on how firms enter international markets. In so doing, we contribute to the recent conversation on how variations in human behavior influence internalization theory

Late Byzantine Mineral Soda High Alumina Glasses from Asia Minor: A New Primary Glass Production Group

The chemical characterisation of archaeological glass allows the discrimination between different glass groups and the identification of raw materials and technological traditions of their production. Several lines of evidence point towards the large-scale production of first millennium CE glass in a limited number of glass making factories from a mixture of Egyptian mineral soda and a locally available silica source. Fundamental changes in the manufacturing processes occurred from the eight/ninth century CE onwards, when Egyptian mineral soda was gradually replaced by soda-rich plant ash in Egypt as well as the Islamic Middle East. In order to elucidate the supply and consumption of glass during this transitional period, 31 glass samples from the assemblage found at Pergamon (Turkey) that date to the fourth to fourteenth centuries CE were analysed by electron microprobe analysis (EPMA) and by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). The statistical evaluation of the data revealed that the Byzantine glasses from Pergamon represent at least three different glass production technologies, one of which had not previously been recognised in the glass making traditions of the Mediterranean. While the chemical characteristics of the late antique and early medieval fragments confirm the current model of glass production and distribution at the time, the elemental make-up of the majority of the eighth- to fourteenth-century glasses from Pergamon indicate the existence of a late Byzantine glass type that is characterised by high alumina levels. Judging from the trace element patterns and elevated boron and lithium concentrations, these glasses were produced with a mineral soda different to the Egyptian natron from the Wadi Natrun, suggesting a possible regional Byzantine primary glass production in Asia Minor

The methylated component of the Neurospora crassa genome

Cytosine methylation is common, but not ubiquitous, in eukaryotes. Mammals (1) and the fungus Neurospora crassa (2,3) have about 2–3% of cytosines methylated. In mammals, methylation is almost exclusively in the under-represented CpG dinucleotides, and most CpGs are methylated (1) whereas in Neurospora, methylation is not preferentially in CpG dinucleotides and the bulk of the genome is unmethylated (4). DNA methylation is essential in mammals (5) but is dispensable in Neurospora (3,6) making this simple eukaryote a favoured organism in which to study methylation. Recent studies indicate that DNA methylation in Neurospora depends on one DNA methyltransferase, DIM-2 (ref. 6), directed by a histone H3 methyltransferase, DIM-5 (ref. 7), but little is known about its cellular and evolutionary functions. As only four methylated sequences have been reported previously in N. crassa, we used methyl-binding-domain agarose chromatography (8) to isolate the methylated component of the genome. DNA sequence analysis shows that the methylated component of the genome consists almost exclusively of relics of transposons that were subject to repeat-induced point mutation—a genome defence system that mutates duplicated sequences (9)