Has the phasing out of stavudine in accordance with changes in WHO guidelines led to a decrease in single-drug substitutions in first-line antiretroviral therapy for HIV in sub-Saharan Africa?

This version is the Accepted Manuscript and is published in final edited form as: AIDS. 2017 January 02; 31(1): 147–157. doi:10.1097/QAD.0000000000001307OBJECTIVE: We assessed the relationship between phasing out stavudine in first-line antiretroviral therapy (ART) in accordance with WHO 2010 policy and single-drug substitutions (SDS) (substituting the nucleoside reverse transcriptase inhibitor in first-line ART) in sub-Saharan Africa. DESIGN: Prospective cohort analysis (International epidemiological Databases to Evaluate AIDS-Multiregional) including ART-naive, HIV-infected patients aged at least 16 years, initiating ART between January 2005 and December 2012. Before April 2010 (July 2007 in Zambia) national guidelines called for patients to initiate stavudine-based or zidovudine-based regimen, whereas thereafter tenofovir or zidovudine replaced stavudine in first-line ART. METHODS: We evaluated the frequency of stavudine use and SDS by calendar year 2004-2014. Competing risk regression was used to assess the association between nucleoside reverse transcriptase inhibitor use and SDS in the first 24 months on ART. RESULTS: In all, 33 441 (8.9%; 95% confience interval 8.7-8.9%) SDS occurred among 377 656 patients in the first 24 months on ART, close to 40% of which were amongst patients on stavudine. The decrease in SDS corresponded with the phasing out of stavudine. Competing risks regression models showed that patients on tenofovir were 20-95% less likely to require a SDS than patients on stavudine, whereas patients on zidovudine had a 75-85% decrease in the hazards of SDS when compared to stavudine. CONCLUSION: The decline in SDS in the first 24 months on treatment appears to be associated with phasing out stavudine for zidovudine or tenofovir in first-line ART in our study. Further efforts to decrease the cost of tenofovir and zidovudine for use in this setting is warranted to substitute all patients still receiving stavudine

Development and validation of the short version of the Psychological General Well-Being Index (PGWB-S)

BACKGROUND: The PGWBI is a 22-item health-related Quality of Life (HRQoL) questionnaire developed in US which produces a self-perceived evaluation of psychological well-being expressed by a summary score. The PGWBI has been validated and used in many countries on large samples of the general population and on specific patient groups. Recently a study was carried out in Italy to reduce the number of items of the original questionnaire, yielding the creation of a shorter validated version of the questionnaire (PGWB-S). The purpose of the present paper is to describe the methods adopted and to report and discuss the relevance of results. METHODS: Data for this study were collected from 4 different population samples: two general population samples a student and a patient sample. On the basis of the results of the first (development) sample population, six relevant items were identified statistically from the original questionnaire and grouped to assemble a new summary scale. Following the newly created 6-item questionnaire was administered in three independent population samples. Descriptive statistics, correlation coefficients, univariate and multivariate regression analyses were used to compare the performance of the long and short questionnaire, within and between population samples and across relevant subgroups. A further independent sample extracted by an ongoing cancer clinical trial served as final validation step. RESULTS: Overall, the questionnaires were administered to 1443 subjects. Six items were selected by a step-wise approach to explain 90% of the variance of the summary measure of the original questionnaire. Response rates reached 100%, while missing items were not observed. University students (n = 400) showed the highest mean value of the summary measure (75.3); while the patient sample (n = 28) had the lowest score (71.5). The correlation coefficients between the summary measures and the single items according to the different studies were satisfactory, reaching the highest estimates in the student sample. The internal consistency showed high values of the Cronbach's alpha coefficient (range 0.80 – 0.92) for all three study samples, coming close to the value of the coefficient established for the original questionnaire (0.94). A cross-validation in an independent sample of 755 cancer patients confirmed the item selection procedure and amount of variance explained by the new shorter questionnaire (ranging from 90. 2 to 95.1 %, across age and sex strata). CONCLUSION: The newly identified PGWB-S showed good acceptability and validity for the use in various settings in Italy. The translation of the PGWB-S into different languages, and its use in other linguistic settings will add evidence about its cross-cultural validity

Standardized and reproducible measurement of decision-making in mice

Progress in science requires standardized assays whose results can be readily shared, compared, and reproduced across laboratories. Reproducibility, however, has been a concern in neuroscience, particularly for measurements of mouse behavior. Here we show that a standardized task to probe decision-making in mice produces reproducible results across multiple laboratories. We designed a task for head-fixed mice that combines established assays of perceptual and value-based decision making, and we standardized training protocol and experimental hardware, software, and procedures. We trained 140 mice across seven laboratories in three countries, and we collected 5 million mouse choices into a publicly available database. Learning speed was variable across mice and laboratories, but once training was complete there were no significant differences in behavior across laboratories. Mice in different laboratories adopted similar reliance on visual stimuli, on past successes and failures, and on estimates of stimulus prior probability to guide their choices. These results reveal that a complex mouse behavior can be successfully reproduced across multiple laboratories. They establish a standard for reproducible rodent behavior, and provide an unprecedented dataset and open-access tools to study decision-making in mice. More generally, they indicate a path towards achieving reproducibility in neuroscience through collaborative open-science approaches

Zum biochemischen Wirkungsmechanismus des adrenocorticotropen Hormons

Es wird eine Übersicht über zwei Hypothesen und die dazugehörigen Befunde zum Wirkungsmechanismus des adrenocorticotropen Hormons gegeben: 1. Der Gehalt der Nebenniere an cyclischem Adenosinmonophosphat wird durch ACTH erhöht, die stimulierende Wirkung des Hormons auf die Corticoidsynthese wird durch cyclisches Adenosinmonophosphat imitiert. Die Beschleunigung der Corticoidsynthese dürfte allerdings nicht durch eine Aktivierung der Phosphorylase in der Nebenniere erfolgen. 2. Befunde zum biochemischen Mechanismus der Stimulation der Proteinsynthese in der Nebenniere durch ACTH werden referiert. Die Intaktheit der Proteinsynthese der Nebenniere scheint für den steroidogenen Effekt des ACTH Voraussetzung zu sein.Two current hypotheses on the mechanism of action of ACTH are reviewed: 1. The content of cyclic 3,5-adenosine monophosphate of the adrenals is increased by ACTH, and cyclic AMP or ACTH enhance corticoid synthesis. However, stimulation of corticoid synthesis presumably is not mediated by activation of adrenal phosphorylase. 2. Experiments dealing with the biochemical mechanism of the stimulation of adrenal protein synthesis are reviewed. The integrity of the adrenal protein synthesis appears to be necessary for the enhancement of corticoid synthesis by ACTH

Chitosan–Starch–Keratin composites: Improving thermo-mechanical and degradation properties through chemical modification

The lysozyme test shows an improved in the degradability rate, the weight loss of the films at 21 days is reduced from 73 % for chitosan-starch matrix up to 16 % for the composites with 5wt% of quill; but all films show a biodegradable character depending on keratin type and chemical modification. The outstanding properties related to the addition of treated keratin materials show that these natural composites are a remarkable alternative to potentiat-ing chitosan–starch films with sustainable featuresChitosan–starch polymers are reinforced with different keratin materials obtained from chicken feather. Keratin materials are treated with sodium hydroxide; the modified surfaces are rougher in comparison with untreated surfaces, observed by Scanning Electron Microscopy. The results obtained by Differential Scanning Calorimetry show an increase in the endothermic peak related to water evaporation of the films from 92 °C (matrix) up to 102–114 °C (reinforced composites). Glass transition temperature increases from 126 °C in the polymer matrix up to 170–200 °C for the composites. Additionally, the storage modulus in the composites is enhanced up to 1614 % for the composites with modified ground quill, 2522 % for composites with modified long fiber and 3206 % for the composites with modified short fiber. The lysozyme test shows an improved in the degradability rate, the weight loss of the films at 21 days is reduced from 73 % for chitosan-starch matrix up to 16 % for the composites with 5wt% of quill; but all films show a biodegradable character depending on keratin type and chemical modification. The outstanding properties related to the addition of treated keratin materials show that these natural composites are a remarkable alternative to potentiat-ing chitosan–starch films with sustainable featuresUniversidad Autónoma del Estado de México Tecnológico Nacional de México, Instituto Tecnológico de Querétaro Universidad Nacional Autónoma de México Tecnológico Nacional de México, Instituto Tecnológico de Celaya Universidad Autónoma de Cd. Juáre

Ebolavirus Is Internalized into Host Cells via Macropinocytosis in a Viral Glycoprotein-Dependent Manner

Ebolavirus (EBOV) is an enveloped, single-stranded, negative-sense RNA virus that causes severe hemorrhagic fever with mortality rates of up to 90% in humans and nonhuman primates. Previous studies suggest roles for clathrin- or caveolae-mediated endocytosis in EBOV entry; however, ebolavirus virions are long, filamentous particles that are larger than the plasma membrane invaginations that characterize clathrin- or caveolae-mediated endocytosis. The mechanism of EBOV entry remains, therefore, poorly understood. To better understand Ebolavirus entry, we carried out internalization studies with fluorescently labeled, biologically contained Ebolavirus and Ebolavirus-like particles (Ebola VLPs), both of which resemble authentic Ebolavirus in their morphology. We examined the mechanism of Ebolavirus internalization by real-time analysis of these fluorescently labeled Ebolavirus particles and found that their internalization was independent of clathrin- or caveolae-mediated endocytosis, but that they co-localized with sorting nexin (SNX) 5, a marker of macropinocytosis-specific endosomes (macropinosomes). Moreover, the internalization of Ebolavirus virions accelerated the uptake of a macropinocytosis-specific cargo, was associated with plasma membrane ruffling, and was dependent on cellular GTPases and kinases involved in macropinocytosis. A pseudotyped vesicular stomatitis virus possessing the Ebolavirus glycoprotein (GP) also co-localized with SNX5 and its internalization and infectivity were affected by macropinocytosis inhibitors. Taken together, our data suggest that Ebolavirus is internalized into cells by stimulating macropinocytosis in a GP-dependent manner. These findings provide new insights into the lifecycle of Ebolavirus and may aid in the development of therapeutics for Ebolavirus infection

Pleiotropic Roles of a Ribosomal Protein in Dictyostelium discoideum

The cell cycle phase at starvation influences post-starvation differentiation and morphogenesis in Dictyostelium discoideum. We found that when expressed in Saccharomyces cerevisiae, a D. discoideum cDNA that encodes the ribosomal protein S4 (DdS4) rescues mutations in the cell cycle genes cdc24, cdc42 and bem1. The products of these genes affect morphogenesis in yeast via a coordinated moulding of the cytoskeleton during bud site selection. D. discoideum cells that over- or under-expressed DdS4 did not show detectable changes in protein synthesis but displayed similar developmental aberrations whose intensity was graded with the extent of over- or under-expression. This suggested that DdS4 might influence morphogenesis via a stoichiometric effect – specifically, by taking part in a multimeric complex similar to the one involving Cdc24p, Cdc42p and Bem1p in yeast. In support of the hypothesis, the S. cerevisiae proteins Cdc24p, Cdc42p and Bem1p as well as their D. discoideum cognates could be co-precipitated with antibodies to DdS4. Computational analysis and mutational studies explained these findings: a C-terminal domain of DdS4 is the functional equivalent of an SH3 domain in the yeast scaffold protein Bem1p that is central to constructing the bud site selection complex. Thus in addition to being part of the ribosome, DdS4 has a second function, also as part of a multi-protein complex. We speculate that the existence of the second role can act as a safeguard against perturbations to ribosome function caused by spontaneous variations in DdS4 levels