A GROWTH-BASED APPROACH TO THE AUTOMATIC GENERATION OF NAVIGATION MESHES

Providing an understanding of space in game and simulation environments is one of the major challenges associated with moving artificially intelligent characters through these environments. The usage of some form of navigation mesh has become the standard method to provide a representation of the walkable space in game environments to characters moving around in that environment. There is currently no standardized best method of producing a navigation mesh. In fact, producing an optimal navigation mesh has been shown to be an NP-Hard problem. Current approaches are a patchwork of divergent methods all of which have issues either in the time to create the navigation meshes (e.g., the best looking navigation meshes have traditionally been produced by hand which is time consuming), generate substandard quality navigation meshes (e.g., many of the automatic mesh production algorithms result in highly triangulated meshes that pose problems for character navigation), or yield meshes that contain gaps of areas that should be included in the mesh and are not (e.g., existing growth-based methods are unable to adapt to non-axis-aligned geometry and as such tend to provide a poor representation of the walkable space in complex environments). We introduce the Planar Adaptive Space Filling Volumes (PASFV) algorithm, Volumetric Adaptive Space Filling Volumes (VASFV) algorithm, and the Iterative Wavefront Edge Expansion Cell Decomposition (Wavefront) algorithm. These algorithms provide growth-based spatial decompositions for navigation mesh generation in either 2D (PASFV) or 3D (VASFV). These algorithms generate quick (on demand) decompositions (Wavefront), use quad/cube base spatial structures to provide more regular regions in the navigation mesh instead of triangles, and offer full coverage decompositions to avoid gaps in the navigation mesh by adapting to non-axis-aligned geometry. We have shown experimentally that the decompositions offered by PASFV and VASFV are superior both in character navigation ability, number of regions, and coverage in comparison to the existing and commonly used techniques of Space Filling Volumes, Hertel-Melhorn decomposition, Delaunay Triangulation, and Automatic Path Node Generation. Finally, we show that our Wavefront algorithm retains the superior performance of the PASFV and VASFV algorithms while providing faster decompositions that contain fewer degenerate and near degenerate regions. Unlike traditional navigation mesh generation techniques, the PASFV and VASFV algorithms have a real time extension (Dynamic Adaptive Space Filling Volumes, DASFV) which allows the navigation mesh to adapt to changes in the geometry of the environment at runtime. In addition, it is possible to use a navigation mesh for applications above and beyond character path planning and navigation. These multiple uses help to increase the return on the investment in creating a navigation mesh for a game or simulation environment. In particular, we will show how to use a navigation mesh for the acceleration of collision detection

A Dual Function for Prickle in Regulating Frizzled Stability during Feedback-Dependent Amplification of Planar Polarity

The core planar polarity pathway coordinates epithelial cell polarity during animal development, and loss of its activity gives rise to a range of defects, from aberrant morphogenetic cell movements to failure to correctly orient structures, such as hairs and cilia. The core pathway functions via a mechanism involving segregation of its protein components to opposite cells ends, where they form asymmetric intracellular complexes that couple cell-cell polarity. This segregation is a self-organizing process driven by feedback interactions between the core proteins themselves. Despite intense efforts, the molecular pathways underlying feedback have proven difficult to elucidate using conventional genetic approaches. Here we investigate core protein function during planar polarization of the Drosophila wing by combining quantitative measurements of protein dynamics with loss-of-function genetics, mosaic analysis, and temporal control of gene expression. Focusing on the key core protein Frizzled, we show that its stable junctional localization is promoted by the core proteins Strabismus, Dishevelled, Prickle, and Diego. In particular, we show that the stabilizing function of Prickle on Frizzled requires Prickle activity in neighboring cells. Conversely, Prickle in the same cell has a destabilizing effect on Frizzled. This destabilizing activity is dependent on the presence of Dishevelled and blocked in the absence of Dynamin and Rab5 activity, suggesting an endocytic mechanism. Overall, our approach reveals for the first time essential in vivo stabilizing and destabilizing interactions of the core proteins required for self-organization of planar polarity

Virological failure and development of new resistance mutations according to CD4 count at combination antiretroviral therapy initiation

Objectives: No randomized controlled trials have yet reported an individual patient benefit of initiating combination antiretroviral therapy (cART) at CD4 counts > 350 cells/μL. It is hypothesized that earlier initiation of cART in asymptomatic and otherwise healthy individuals may lead to poorer adherence and subsequently higher rates of resistance development. Methods: In a large cohort of HIV-positive individuals, we investigated the emergence of new resistance mutations upon virological treatment failure according to the CD4 count at the initiation of cART. Results: Of 7918 included individuals, 6514 (82.3%), 996 (12.6%) and 408 (5.2%) started cART with a CD4 count ≤ 350, 351-499 and ≥ 500 cells/μL, respectively. Virological rebound occurred while on cART in 488 (7.5%), 46 (4.6%) and 30 (7.4%) with a baseline CD4 count ≤ 350, 351-499 and ≥ 500 cells/μL, respectively. Only four (13.0%) individuals with a baseline CD4 count > 350 cells/μL in receipt of a resistance test at viral load rebound were found to have developed new resistance mutations. This compared to 107 (41.2%) of those with virological failure who had initiated cART with a CD4 count < 350 cells/μL. Conclusions: We found no evidence of increased rates of resistance development when cART was initiated at CD4 counts above 350 cells/μL. HIV Medicin

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials

An amendment to this paper has been published and can be accessed via the original article

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

A growth-based approach to the automatic generation of navigation meshes

Providing an understanding of space in game and simulation environments is one of the major challenges associated with moving artificially intelligent characters through these environments. The usage of some form of navigation mesh has become the standard method to provide a representation of the walkable space in game environments to characters moving around in that environment. There is currently no standardized best method of producing a navigation mesh. In fact, producing an optimal navigation mesh has been shown to be an NP-Hard problem. Current approaches are a patchwork of divergent methods all of which have issues either in the time to create the navigation meshes (e.g., the best looking navigation meshes have traditionally been produced by hand which is time consuming), generate substandard quality navigation meshes (e.g., many of the automatic mesh production algorithms result in highly triangulated meshes that pose problems for character navigation), or yield meshes that contain gaps of areas that should be included in the mesh and are not (e.g., existing growth-based methods are unable to adapt to non-axis-aligned geometry and as such tend to provide a poor representation of the walkable space in complex environments). We introduce the Planar Adaptive Space Filling Volumes (PASFV) algorithm, Volumetric Adaptive Space Filling Volumes (VASFV) algorithm, and the Iterative Wavefront Edge Expansion Cell Decomposition (Wavefront) algorithm. These algorithms provide growth-based spatial decompositions for navigation mesh generation in either 2D (PASFV) or 3D (VASFV). These algorithms generate quick (on demand) decompositions (Wavefront), use quad/cube base spatial structures to provide more regular regions in the navigation mesh instead of triangles, and offer full coverage decompositions to avoid gaps in the navigation mesh by adapting to non-axis-aligned geometry. We have shown experimentally that the decompositions offered by PASFV and VASFV are superior both in character navigation ability, number of regions, and coverage in comparison to the existing and commonly used techniques of Space Filling Volumes, Hertel-Melhorn decomposition, Delaunay Triangulation, and Automatic Path Node Generation. Finally, we show that our Wavefront algorithm retains the superior performance of the PASFV and VASFV algorithms while providing faster decompositions that contain fewer degenerate and near degenerate regions. Unlike traditional navigation mesh generation techniques, the PASFV and VASFV algorithms have a real time extension (Dynamic Adaptive Space Filling Volumes, DASFV) which allows the navigation mesh to adapt to changes in the geometry of the environment at runtime. In addition, it is possible to use a navigation mesh for applications above and beyond character path planning and navigation. These multiple uses help to increase the return on the investment in creating a navigation mesh for a game or simulation environment. In particular, we will show how to use a navigation mesh for the acceleration of collision detection