Treatment exhaustion of highly active antiretroviral therapy (HAART) among individuals infected with HIV in the United Kingdon: multicentre cohort study

Objectives: To investigate whether there is evidence that an increasing proportion of HIV infected patients is starting to experience increases in viral load and decreases in CD4 cell count that are consistent with exhaustion of available treatment options. Design: Multicentre cohort study. Setting: Six large HIV treatment centres in southeast England. Participants: All individuals seen for care between 1 January 1996 and 31 December 2002. Main outcome measures: Exposure to individual antiretroviral drugs and drug classes, CD4 count, plasma HIV RNA burden. Results: Information is available on 16 593 individuals (13 378 (80.6%) male patients, 10 340 (62.3%) infected via homosexual or bisexual sex, 4426 (26.7%) infected via heterosexual sex, median age 34 years). Overall, 10 207 of the 16 593 patients (61.5%) have been exposed to any antiretroviral therapy. This proportion increased from 41.2% of patients under follow up at the end of 1996 to 71.3% of those under follow up in 2002. The median CD4 count and HIV RNA burden of patients under follow up in each year changed from 270 cells/mm3 and 4.34 log10 copies/ml in 1996 to 408 cells/mm3 and 1.89 log10 copies/ml, respectively, in 2002. By 2002, 3060 (38%) of patients who had ever been treated with antiretroviral therapy had experienced all three main classes. Of these, around one quarter had evidence of “viral load failure” with all these three classes. Patients with three class failure were more likely to have an HIV RNA burden > 2.7 log10 copies/ml and a CD4 count < 200 cells/mm3. Conclusions: The proportion of individuals with HIV infection in the United Kingdom who have been treated has increased gradually over time. A substantial proportion of these patients seem to be in danger of exhausting their options for antiretroviral treatment. New drugs with low toxicity, which are not associated with cross resistance to existing drugs, are urgently needed for such patients

Validating Requirements for Fault Tolerant Systems Using Model Checking

Model checking is shown to be an effective tool in validating the behavior of a fault tolerant embedded spacecraft controller. The case study presented here shows that by judiciously abstracting away extraneous complexity, the state space of the model could be exhaustively searched allowing critical functional requirements to be validated down to the design level. Abstracting away detail not germane to the problem of interest leaves by definition a partial specification behind. The success of this procedure shows that it is feasible to effectively validate a partial specification with this technique. Three anomalies were found in the system one of which is an error in the detailed requirements, and the other two are missing/ambiguous requirements. Because the method allows validation of partial specifications, it also is an effective methodology towards maintaining fidelity between a co-evolving specification and an implementation

Efficient search, mapping, and optimization of multi-protein genetic systems in diverse bacteria

Developing predictive models of multi-protein genetic systems to understand and optimize their behavior remains a combinatorial challenge, particularly when measurement throughput is limited. We developed a computational approach to build predictive models and identify optimal sequences and expression levels, while circumventing combinatorial explosion. Maximally informative genetic system variants were first designed by the RBS Library Calculator, an algorithm to design sequences for efficiently searching a multi-protein expression space across a > 10,000-fold range with tailored search parameters and well-predicted translation rates. We validated the algorithm's predictions by characterizing 646 genetic system variants, encoded in plasmids and genomes, expressed in six gram-positive and gram-negative bacterial hosts. We then combined the search algorithm with system-level kinetic modeling, requiring the construction and characterization of 73 variants to build a sequence-expression-activity map (SEAMAP) for a biosynthesis pathway. Using model predictions, we designed and characterized 47 additional pathway variants to navigate its activity space, find optimal expression regions with desired activity response curves, and relieve rate-limiting steps in metabolism. Creating sequence-expression-activity maps accelerates the optimization of many protein systems and allows previous measurements to quantitatively inform future designs

Computer Games Are Serious Business and so is their Quality: Particularities of Software Testing in Game Development from the Perspective of Practitioners

Over the last several decades, computer games started to have a significant impact on society. However, although a computer game is a type of software, the process to conceptualize, produce and deliver a game could involve unusual features. In software testing, for instance, studies demonstrated the hesitance of professionals to use automated testing techniques with games, due to the constant changes in requirements and design, and pointed out the need for creating testing tools that take into account the flexibility required for the game development process. Goal. This study aims to improve the current body of knowledge regarding software testing in game development and point out the existing particularities observed in software testing considering the development of a computer game. Method. A mixed-method approach based on a case study and an opinion survey was applied to collect quantitative and qualitative data from software professionals regarding the particularities of software testing in game development. Results. We analyzed over 70 messages posted on three well-established network of question-and-answer communities related to software engineering, software testing and game development and received answers of 38 professionals discussing differences between testing a computer game and a general software, and identified important aspects to be observed by practitioners in the process of planning, performing and reporting tests in this context. Conclusion. Considering computer games, software testing must focus not only on the common aspects of a general software, but also, track and investigate issues that could be related to game balance, game physics and entertainment related-aspects to guarantee the quality of computer games and a successful testing process

Accounting for unequal access to higher education: the role of social identity factors

Western societies stress the potential for anyone, irrespective of social background, to improve their position within society. However, disadvantaged students face barriers in gaining a good education. Two studies in secondary schools show how perceptions of identity compatibility and anticipated fit influence students’ university choices. It was found that relatively disadvantaged students scored lower on identity compatibility, and that low scores on identity compatibility were associated with lower anticipated fit at a local selective (Study 1) or highly selective (Study 2) university. Anticipated fit, in turn, predicted the type of university to which participants wanted to apply; those who anticipated fitting in more at selective universities were more likely to apply to higher status universities. These relations were significant while controlling for academic achievement. Together, these studies suggest that social identity factors play a relevant role in explaining higher education choices among low-status group members

The relationships between internal and external threat and right-wing attitudes: A three-wave longitudinal study

The interplay between threat and right-wing attitudes has received much research attention, but its longitudinal relationship has hardly been investigated. In this study, we investigated the longitudinal relationships between internal and external threat and right-wing attitudes using a cross-lagged design at three different time points in a large nationally representative sample (N = 800). We found evidence for bidirectional relationships. Higher levels of external threat were related to higher levels of Right-Wing Authoritarianism and to both the egalitarianism and dominance dimensions of Social Dominance Orientation at a later point in time. Conversely, higher levels of RWA were also related to increased perception of external threat later in time. Internal threat did not yield significant direct or indirect longitudinal relationships with right-wing attitudes. Theoretical and practical implications of these longitudinal effects are discussed

High-resolution characterisation of short-term temporal variability in the taxonomic and resistome composition of wastewater influent

Wastewater-based epidemiology (WBE) for population-level surveillance of antimicrobial resistance (AMR) is gaining significant traction, but the impact of wastewater sampling methods on results is unclear. In this study, we characterized taxonomic and resistome differences between single-timepoint-grab and 24 h composites of wastewater influent from a large UK-based wastewater treatment work [WWTW (population equivalent: 223435)]. We autosampled hourly influent grab samples (n=72) over three consecutive weekdays, and prepared additional 24 h composites (n=3) from respective grabs. For taxonomic profiling, metagenomic DNA was extracted from all samples and 16S rRNA gene sequencing was performed. One composite and six grabs from day 1 underwent metagenomic sequencing for metagenomic dissimilarity estimation and resistome profiling. Taxonomic abundances of phyla varied significantly across hourly grab samples but followed a repeating diurnal pattern for all 3days. Hierarchical clustering grouped grab samples into four time periods dissimilar in both 16S rRNA gene-based profiles and metagenomic distances. 24H-composites resembled mean daily phyla abundances and showed low variability of taxonomic profiles. Of the 122 AMR gene families (AGFs) identified across all day 1 samples, single grab samples identified a median of six (IQR: 5–8) AGFs not seen in the composite. However, 36/36 of these hits were at lateral coverage <0.5 (median: 0.19; interquartile range: 0.16–0.22) and potential false positives. Conversely, the 24H-composite identified three AGFs not seen in any grab with higher lateral coverage (0.82; 0.55–0.84). Additionally, several clinically significant human AGFs (blaVIM, blaIMP, blaKPC) were intermittently or completely missed by grab sampling but captured by the 24 h composite. Wastewater influent undergoes significant taxonomic and resistome changes on short timescales potentially affecting interpretation of results based on sampling strategy. Grab samples are more convenient and potentially capture low-prevalence/transient targets but are less comprehensive and temporally variable. Therefore, we recommend 24H-composite sampling where feasible. Further validation and optimization of WBE methods is vital for its development into a robust AMR surveillance approach