Week 96 efficacy and safety results of the phase 3, randomized EMERALD trial to evaluate switching from boosted-protease inhibitors plus emtricitabine/tenofovir disoproxil fumarate regimens to the once daily, single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in treatment-experienced, virologically-suppressed adults living with HIV-1

Altres ajuts: This study was sponsored by Janssen.Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated through 96 weeks in EMERALD (NCT02269917). Virologically-suppressed, HIV-1-positive treatment-experienced adults (previous non-darunavir virologic failure [VF] allowed) were randomized (2:1) to D/C/F/TAF or boosted protease inhibitor (PI) plus emtricitabine/tenofovir-disoproxil-fumarate (F/TDF) over 48 weeks. At week 52 participants in the boosted PI arm were offered switch to D/C/F/TAF (late-switch, 44 weeks D/C/F/TAF exposure). All participants were followed on D/C/F/TAF until week 96. Efficacy endpoints were percentage cumulative protocol-defined virologic rebound (PDVR; confirmed viral load [VL] ≥50 copies/mL) and VL < 50 copies/mL (virologic suppression) and ≥50 copies/mL (VF) (FDA-snapshot analysis). Of 1141 randomized patients, 1080 continued in the extension phase. Few patients had PDVR (D/C/F/TAF: 3.1%, 24/763 cumulative through week 96; late-switch: 2.3%, 8/352 week 52-96). Week 96 virologic suppression was 90.7% (692/763) (D/C/F/TAF) and 93.8% (330/352) (late-switch). VF was 1.2% and 1.7%, respectively. No darunavir, primary PI, tenofovir or emtricitabine resistance-associated mutations were observed post-baseline. No patients discontinued for efficacy-related reasons. Few discontinued due to adverse events (2% D/C/F/TAF arm). Improved renal and bone parameters were maintained in the D/C/F/TAF arm and observed in the late-switch arm, with small increases in total cholesterol/high-density-lipoprotein-cholesterol ratio. A study limitation was the lack of a control arm in the week 96 analysis. Through 96 weeks, D/C/F/TAF resulted in low PDVR rates, high virologic suppression rates, very few VFs, and no resistance development. Late-switch results were consistent with D/C/F/TAF week 48 results. EMERALD week 96 results confirm the efficacy, high genetic barrier to resistance and safety benefits of D/C/F/TAF

Severe effects of long-term drought on calcareous grassland seed banks

Climate change models project shifts in precipitation patterns at regional and global scales. Increases in dry areas and the occurrence of drought predicted in future scenarios are likely to threaten grassland ecosystems. Calcareous grassland seed banks have proven to be resistant to short-term drought, but their responses to long-term drought are unknown. Here we show that 14 years of summer drought changed calcareous grassland seed bank composition, reducing its size and richness, and that these responses do not simply reflect patterns in the above-ground vegetation. Moreover, the effect of drought was larger on seed banks than on vegetation, and above-ground responses mediated by soil depth were less evident in the seed bank than in the vegetation. These results demonstrate that the severity of drought effects on calcareous grasslands is larger than previously thought, and show that this ecosystem is highly vulnerable and has low resilience to predicted decreases in soil moisture

Week 96 efficacy and safety results of the phase 3, randomized EMERALD trial to evaluate switching from boosted-protease inhibitors plus emtricitabine/tenofovir disoproxil fumarate regimens to the once daily, single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in treatment-experienced, virologically-suppressed adults living with HIV-1

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated through 96 weeks in EMERALD (NCT02269917). Virologically-suppressed, HIV-1-positive treatment-experienced adults (previous non-darunavir virologic failure [VF] allowed) were randomized (2:1) to D/C/F/TAF or boosted protease inhibitor (PI) plus emtricitabine/tenofovir-disoproxil-fumarate (F/TDF) over 48 weeks. At week 52 participants in the boosted PI arm were offered switch to D/C/F/TAF (late-switch, 44 weeks D/C/F/TAF exposure). All participants were followed on D/C/F/TAF until week 96. Efficacy endpoints were percentage cumulative protocol-defined virologic rebound (PDVR; confirmed viral load [VL] ≥50 copies/mL) and VL < 50 copies/mL (virologic suppression) and ≥50 copies/mL (VF) (FDA-snapshot analysis). Of 1141 randomized patients, 1080 continued in the extension phase. Few patients had PDVR (D/C/F/TAF: 3.1%, 24/763 cumulative through week 96; late-switch: 2.3%, 8/352 week 52–96). Week 96 virologic suppression was 90.7% (692/763) (D/C/F/TAF) and 93.8% (330/352) (late-switch). VF was 1.2% and 1.7%, respectively. No darunavir, primary PI, tenofovir or emtricitabine resistance-associated mutations were observed post-baseline. No patients discontinued for efficacy-related reasons. Few discontinued due to adverse events (2% D/C/F/TAF arm). Improved renal and bone parameters were maintained in the D/C/F/TAF arm and observed in the late-switch arm, with small increases in total cholesterol/high-density-lipoprotein-cholesterol ratio. A study limitation was the lack of a control arm in the week 96 analysis. Through 96 weeks, D/C/F/TAF resulted in low PDVR rates, high virologic suppression rates, very few VFs, and no resistance development. Late-switch results were consistent with D/C/F/TAF week 48 results. EMERALD week 96 results confirm the efficacy, high genetic barrier to resistance and safety benefits of D/C/F/TAF

Solving Impartial SET Using Knowledge and Combinatorial Game Theory

Standard SET is a card game played between any number of players moving simultaneously, where a move means taking a number of cards obeying some predetermined conditions (a Set). It is mainly a game of pattern recognition and speed. The winner is the player obtaining the most Sets. To enable analyzing SET in a more mathematical and game-theoretic sense we transformed the game into an impartial combinatorial game. SET versions may differ depending on the number of characteristics c on the cards and the number of values v of each characteristic. We indicate a particular version of SET for some v and c as SET-v-c. We analyze different versions of Impartial SET using aß search with several enhancements from mathematical SET theory and from Combinatorial Game Theory. We first show using SET theory that all SET-2-c versions for c&gt; 1 are second-player wins and that SET-v-2 versions are first-player wins for odd v and second-player wins for even v. We next show how to compute solutions using search. We give some results and discuss how solving efficiencies were dependent on the enhancements used. Especially, the use of a pruning method based on symmetry of positions was pivotal for a large efficiency enhancement. Also the use of two methods based on endgame databases filled with Combinatorial Game Theory values proved very useful in further enhancing the solving efficiency. Using all enhancements together the complex SET-4-3 game was solved, needing the investigation of some 2 billion nodes. This game is (maybe counterintuitive) a first-player win

Extended data for Grammar-Based Action Selection Rules for Scriptless Testing

&lt;p&gt;Extended data for the paper Grammar-Based Action Selection Rules for Scriptless Testing&lt;/p&gt

IVVES (Industrial-Grade Verification and Validation of Evolving Systems)

Anincreasing numberofinformationsystemsarebasedonmachinelearning(ML)orartificialintelligence (AI). In some cases, the systems are adapting their behaviour during operation based on the data being gathered. This introduces new challenges for verification, validation and software testing. The traditional way of testing the systems during the development and before the deployment does not suffice anymore. IVVES (Industrial-Grade Verification and Validation of Evolving Systems) project aims to address these challenges by researching and developing methods to test ML and AI solutions and evolving systems, and using AI and ML to improve and automate development and testing. We summarise the results of the project at a high level, and provide more details on the research and collaboration related to scriptless end-to-end testing through graphical user interface

IVVES (Industrial-Grade Verification and Validation of Evolving Systems)

Anincreasing numberofinformationsystemsarebasedonmachinelearning(ML)orartificialintelligence (AI). In some cases, the systems are adapting their behaviour during operation based on the data being gathered. This introduces new challenges for verification, validation and software testing. The traditional way of testing the systems during the development and before the deployment does not suffice anymore. IVVES (Industrial-Grade Verification and Validation of Evolving Systems) project aims to address these challenges by researching and developing methods to test ML and AI solutions and evolving systems, and using AI and ML to improve and automate development and testing. We summarise the results of the project at a high level, and provide more details on the research and collaboration related to scriptless end-to-end testing through graphical user interface

Week 96 results of a phase 3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients

BACKGROUND: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated through 96 weeks in AMBER (NCT02431247). METHODS: Treatment-naive, HIV-1-positive adults [screening plasma viral load ≥1000 copies/ml; CD4 cell count >50 cells/μl) were randomized (1 : 1) to D/C/F/TAF (N = 362) or D/C plus emtricitabine/tenofovir-disoproxil-fumarate (F/TDF) (N = 363) over at least 48 weeks. After week 48, patients could continue on or switch to D/C/F/TAF in an open-label extension phase until week 96. RESULTS: At week 96, D/C/F/TAF exposure was 626 patient-years (D/C/F/TAF arm) and 109 patient-years (control arm post switch), week 96 virologic suppression (viral load <50 copies/ml; FDA-Snapshot, from baseline) was 85.1% (308/362) (D/C/F/TAF) and 83.7% (304/363) (control). Week 96 virologic failure (viral load ≥50 copies/ml; FDA-Snapshot) was 5.5% (20/362) and 4.4% (16/363), respectively. No darunavir, primary protease inhibitor or tenofovir resistance-associated mutations (RAMs) were observed post baseline. In one patient in each arm, an M184I and/or V RAM was detected. Few adverse event-related discontinuations (3% D/C/F/TAF; <1% control post switch) and no deaths occurred on D/C/F/TAF. Improved renal and bone parameters were maintained in the D/C/F/TAF arm and observed in the control arm post switch. Increases in total-cholesterol/high-density-lipoprotein--cholesterol rtio at week 96 were +0.25 versus baseline (D/C/F/TAF) and +0.24 versus switch (control). CONCLUSION: At week 96, D/C/F/TAF resulted in high virologic response and low virologic failure rates, with no resistance development to darunavir or TAF/TDF. Bone, renal and lipid safety were consistent with known D/C/F/TAF component profiles. Control arm safety post switch was consistent with the D/C/F/TAF arm. AMBER week 96 results confirm the efficacy, high barrier to resistance and bone/renal safety benefits of D/C/F/TAF for treatment-naive patients