The Meaning of Adherence When Behavioral Risk Patterns Vary: Obscured Use- and Method-Effectiveness in HIV-Prevention Trials

Background

Recently promising trials of innovative biomedical approaches to prevent HIV transmission have been reported. Participants'' non-adherence to the prevention methods complicates the analyses and interpretation of trial results. The influence of variable sexual behaviors within and between participants of trials further obscures matters. Current methodological and statistical approaches in HIV-prevention studies, as well as ongoing debates on contradictory trial results, may fail to accurately address these topics.

Methodology/Principal Findings

Through developing a cumulative probability model of infection within HIV prevention trials, we demonstrate how adherence and sexual behavior patterns impact the overall estimate of effectiveness, the effectiveness of prevention methods as a function of adherence, and conclusions about methods'' true effectiveness. Applying the model to summary-level data from the CAPRISA trial, we observe markedly different values for the true method effectiveness of the microbicide, and show that if the gel would have been tested among women with slightly different sexual behavior patterns, conclusions might well have been that the gel is not effective.

Conclusions/Significance

Relative risk and adherence analyses in HIV prevention trials overlook the complex interplay between adherence and sexual behavior patterns. Consequently, they may not provide accurate estimates of use- and method-effectiveness. Moreover, trial conclusions are contingent upon the predominant sexual behavior pattern of participants and cannot be directly generalized to other contexts. We recommend researchers to (re)examine their data and use the cumulative probability model to estimate the true method effectiveness, which might contribute to resolving current questions about contradictory trial results. Moreover, we suggest taking into account the issues raised in the design of future trials and in population models estimating the impact of large-scale dissemination of prevention methods. Comprehension of the topics described will help readers to better interpret (apparently contradictory) trial outcomes.     

Intérêt du dosage de la chromogranine A sérique dans le suivi des phéochromocytomes

This study aimed at comparing the role of serum chromogranine A (CGA) over 24-h urinary total normetanephrine (NTU) and plasma concentration total normetanephrine (NTP) in the recurrence of phaeochromocytomas. A new approach focusing on the increase rate over time of CGA was studied on 24 patients with abdominal phaeochromocytoma after surgery. In the first group, 15 had a benign sporadic disease without any sign of recurrence during follow-up. In the second group, nine had recurrence from a benign or a malignant, intra- or extra-adrenal phaeochromocytoma. The evolution of CGA rates was significantly different within the two groups during follow-up (p = 0.025). A new approach of the CGA values, based on its evolution over time, showed an excellent ability to identify recurrence with an excellent accuracy. This new parameter enabled to correctly diagnose all patients with recurrence, whereas NTU and NTP failed in four patients. Finally, CGA, but above all its increase rate, may be an early marker of recurrence. CGA should be associated to NTU and NTP during follow-up as its assay is less prone to interference and easier to perform.     

The glycerol channel Fps1p mediates the uptake of arsenite and antimonite in Saccharomyces cerevisiae

The Saccharomyces cerevisiae FPS1 gene encodes a glycerol channel protein involved in osmoregulation. We present evidence that Fps1p mediates influx of the trivalent metalloids arsenite and antimonite in yeast. Deletion of FPS1 improves tolerance to arsenite and potassium antimonyl tartrate. Under high osmolarity conditions, when the Fps1p channel is closed, wild-type cells show the same degree of As(III) and Sb(III) tolerance as the fps1Delta mutant. Additional deletion of FPS1 in mutants defective in arsenite and antimonite detoxification partially suppresses their hypersensitivity to metalloid salts. Cells expressing a constitutively open form of the Fps1p channel are highly sensitive to both arsenite and antimonite. We also show by direct transport assays that arsenite uptake is mediated by Fps1p. Yeast cells appear to control the Fps1p-mediated pathway of metalloid uptake, as expression of the FPS1 gene is repressed upon As(III) and Sb(III) addition. To our knowledge, this is the first report describing a eukaryotic uptake mechanism for arsenite and antimonite and its involvement in metalloid tolerance.     

Mapping global cropland and field size

A new 1 km global IIASA‐IFPRI cropland percentage map for the baseline year 2005 has been developed which integrates a number of individual cropland maps at global to regional to national scales. The individual map products include existing global land cover maps such as GlobCover 2005 and MODIS v.5, regional maps such as AFRICOVER and national maps from mapping agencies and other organizations. The different products are ranked at the national level using crowdsourced data from Geo‐Wiki to create a map that reflects the likelihood of cropland. Calibration with national and subnational crop statistics was then undertaken to distribute the cropland within each country and subnational unit. The new IIASA‐IFPRI cropland product has been validated using very high‐resolution satellite imagery via Geo‐Wiki and has an overall accuracy of 82.4%. It has also been compared with the EarthStat cropland product and shows a lower root mean square error on an independent data set collected from Geo‐Wiki. The first ever global field size map was produced at the same resolution as the IIASA‐IFPRI cropland map based on interpolation of field size data collected via a Geo‐Wiki crowdsourcing campaign. A validation exercise of the global field size map revealed satisfactory agreement with control data, particularly given the relatively modest size of the field size data set used to create the map. Both are critical inputs to global agricultural monitoring in the frame of GEOGLAM and will serve the global land modelling and integrated assessment community, in particular for improving land use models that require baseline cropland information. These products are freely available for downloading from the http://cropland.geo-wiki.org website.     

Gallium nitrate induces fibrinogen flocculation: an explanation for its hemostatic effect?

A novel hemostatic effect of gallium nitrate has recently been discovered. Our aim was to perform a preliminary investigation into its mode of action. Thromboelastography^® showed no effect on coagulation but pointed instead to changes in fibrinogen concentration. We measured functional fibrinogen in whole blood after addition of gallium nitrate and nitric acid. We found that gallium nitrate induces fibrinogen precipitation in whole blood to a significantly higher degree than solutions of nitric acid alone. This precipitate is not primarily pH driven, and appears to occur via flocculation. This behavior is in line with the generally observed ability of metals to induce fibrinogen precipitation. Further investigation is required into this novel phenomenon.     

Membrane fission by dynamin: what we know and what we need to know

The large GTPase dynamin is the first protein shown to catalyze membrane fission. Dynamin and its related proteins are essential to many cell functions, from endocytosis to organelle division and fusion, and it plays a critical role in many physiological functions such as synaptic transmission and muscle contraction. Research of the past three decades has focused on understanding how dynamin works. In this review, we present the basis for an emerging consensus on how dynamin functions. Three properties of dynamin are strongly supported by experimental data: first, dynamin oligomerizes into a helical polymer; second, dynamin oligomer constricts in the presence of GTP; and third, dynamin catalyzes membrane fission upon GTP hydrolysis. We present the two current models for fission, essentially diverging in how GTP energy is spent. We further discuss how future research might solve the remaining open questions presently under discussion.     

Torsional regulation of hRPA-induced unwinding of double-stranded DNA

All cellular single-stranded (ss) DNA is rapidly bound and stabilized by single stranded DNA-binding proteins (SSBs). Replication protein A, the main eukaryotic SSB, is able to unwind double-stranded (ds) DNA by binding and stabilizing transiently forming bubbles of ssDNA. Here, we study the dynamics of human RPA (hRPA) activity on topologically constrained dsDNA with single-molecule magnetic tweezers. We find that the hRPA unwinding rate is exponentially dependent on torsion present in the DNA. The unwinding reaction is self-limiting, ultimately removing the driving torsional stress. The process can easily be reverted: release of tension or the application of a rewinding torque leads to protein dissociation and helix rewinding. Based on the force and salt dependence of the in vitro kinetics we anticipate that the unwinding reaction occurs frequently in vivo. We propose that the hRPA unwinding reaction serves to protect and stabilize the dsDNA when it is structurally destabilized by mechanical stresses.