10 Years of GWAS in intraocular pressure

Intraocular pressure (IOP) is the only modifiable risk factor for glaucoma, the leading cause of irreversible blindness worldwide. In this review, we summarize the findings of genome-wide association studies (GWASs) of IOP published in the past 10 years and prior to December 2022. Over 190 genetic loci and candidate genes associated with IOP have been uncovered through GWASs, although most of these studies were conducted in subjects of European and Asian ancestries. We also discuss how these common variants have been used to derive polygenic risk scores for predicting IOP and glaucoma, and to infer causal relationship with other traits and conditions through Mendelian randomization. Additionally, we summarize the findings from a recent large-scale exome-wide association study (ExWAS) that identified rare variants associated with IOP in 40 novel genes, six of which are drug targets for clinical treatment or are being evaluated in clinical trials. Finally, we discuss the need for future genetic studies of IOP to include individuals from understudied populations, including Latinos and Africans, in order to fully characterize the genetic architecture of IOP

Response to rituximab induction is a predictive marker in B-cell post-transplant lymphoproliferative disorder and allows successful stratification into rituximab or r-chop consolidation in an international, prospective, multicenter Phase II trial

Purpose The Sequential Treatment of CD20-Positive Posttransplant Lymphoproliferative Disorder (PTLD-1) trial ( ClinicalTrials.gov identifier, NCT01458548) established sequential treatment with four cycles of rituximab followed by four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy as a standard in the management of post-transplant lymphoproliferative disorder (PTLD) and identified response to rituximab induction as a prognostic factor for overall survival. We hypothesized that rituximab consolidation might be sufficient treatment for patients with a complete response after rituximab induction. Patients and Methods In this prospective, international, multicenter phase II trial, 152 treatment-naive adult solid organ transplant recipients, with CD20+ PTLD unresponsive to immunosuppression reduction, were treated with four weekly doses of rituximab induction. After restaging, complete responders continued with four courses of rituximab consolidation every 21 days; all others received four courses of rituximab plus CHOP chemotherapy every 21 days. The primary end point was treatment efficacy measured as the response rate in patients who completed therapy and the response duration in those who completed therapy and responded. Secondary end points were frequency of infections, treatment-related mortality, and overall survival in the intention-to-treat population. Results One hundred eleven of 126 patients had a complete or partial response (88%; 95% CI, 81% to 93%), of whom 88 had a complete response (70%; 95% CI, 61% to 77%). Median response duration was not reached. The 3-year estimate was 82% (95% CI, 74% to 90%). Median overall survival was 6.6 years (95% CI, 5.5 to 7.6 years). The frequency of grade 3 or 4 infections and of treatment-related mortality was 34% (95% CI, 27% to 42%) and 8% (95% CI, 5% to 14%), respectively. Response to rituximab induction remained a prognostic factor for overall survival despite treatment stratification. Conclusion In B-cell PTLD, treatment stratification into rituximab or rituximab plus CHOP consolidation on the basis of response to rituximab induction is feasible, safe, and effective

Surprisingly Simple Mechanical Behavior of a Complex Embryonic Tissue

Background: Previous studies suggest that mechanical feedback could coordinate morphogenetic events in embryos. Furthermore, embryonic tissues have complex structure and composition and undergo large deformations during morphogenesis. Hence we expect highly non-linear and loading-rate dependent tissue mechanical properties in embryos. Methodology/Principal Findings: We used micro-aspiration to test whether a simple linear viscoelastic model was sufficient to describe the mechanical behavior of gastrula stage Xenopus laevis embryonic tissue in vivo. We tested whether these embryonic tissues change their mechanical properties in response to mechanical stimuli but found no evidence of changes in the viscoelastic properties of the tissue in response to stress or stress application rate. We used this model to test hypotheses about the pattern of force generation during electrically induced tissue contractions. The dependence of contractions on suction pressure was most consistent with apical tension, and was inconsistent with isotropic contraction. Finally, stiffer clutches generated stronger contractions, suggesting that force generation and stiffness may be coupled in the embryo. Conclusions/Significance: The mechanical behavior of a complex, active embryonic tissue can be surprisingly well described by a simple linear viscoelastic model with power law creep compliance, even at high deformations. We found no evidence of mechanical feedback in this system. Together these results show that very simple mechanical models can be useful in describing embryo mechanics. © 2010 von Dassow et al

Evaluating Functional Dispersal in a Nest Ectoparasite and Its Eco-Epidemiological Implications

International audienc

Numerical analysis of a finite volume scheme for a seawater intrusion model with cross-diffusion in an unconfined aquifer

We consider a degenerate parabolic system modeling the flow of fresh and saltwater in a porous medium in the context of seawater intrusion. We propose and analyze a finite volume scheme based on two-point flux approximation with upwind mobilities. The scheme preserves at the discrete level the main features of the continuous problem, namely the nonnegativity of the solutions, the decay of the energy and the control of the entropy and its dissipation. Based on these nonlinear stability results, we show that the scheme converges towards a weak solution to the problem. Numerical results are provided to illustrate the behavior of the model and of the scheme

Evaluating functional dispersal and its eco-epidemiological implications in a nest ectoparasite. Reviewed and recommended by Peer Community In Ecology (https://dx.doi.org/10.24072/pci.ecology.100013)

International audienceFunctional dispersal (between-site movement, with or without subsequent reproduction) is a key trait acting on the ecological and evolutionary trajectories of a species, with potential cascading effects on other members of the local community. It is often difficult to quantify, and particularly so for small organisms such as parasites. Understanding this life history trait can help us identify the drivers of population dynamics and, in the case of vectors, the circulation of associated infectious agents. In the present study, functional dispersal of the soft tick Ornithodoros maritimus was studied at small scale, within a colony of yellow-legged-gulls (Larus michahellis). Previous work showed a random distribution of infectious agents in this tick at the within-colony scale, suggesting frequent tick movement among nests. This observation contrasts with the presumed strong endophilic nature described for this tick group. By combining an experimental field study, where both nest success and tick origin were manipulated, with Capture-Mark-Recapture modeling, dispersal rates between nests were estimated taking into account both tick capture probability and survival, and considering an effect of tick sex. As expected, tick survival probability was higher in successful nests, where hosts were readily available for the blood meal, than in unsuccessful nests, but capture probability was lower. Dispersal was low overall, regardless of nest state or tick sex, and there was no evidence for tick homing behavior; ticks from foreign nests did not disperse more than ticks in their nest of origin. These results confirm the strong endophilic nature of this tick species, highlighting the importance of life cycle plasticity for adjusting to changes in host availability. However, results also raise questions with respect to the previously described within-colony distribution of infectious agents in ticks, suggesting that tick dispersal either occurs over longer temporal scales and/or that transient host movements outside the breeding period result in vector exposure to a diverse range of infectious agents

Natal colony influences age-specific movement patterns of the Yellow-legged gull (Larus michahellis)

International audienceBackground As for other life history traits, variation occurs in movement patterns with important impacts on population demography and community interactions. Individuals can show variation in the extent of seasonal movement (or migration) or can change migratory routes among years. Internal factors, such as age or body condition, may strongly influence changes in movement patterns. Indeed, young individuals often tend to move across larger spatial scales compared to adults, but relatively few studies have investigated the proximate and ultimate factors driving such variation. This is particularly the case for seabirds in which the sub-adult period is long and difficult to follow. Here, we examine migration variation and the factors that affect it in a common Mediterranean seabird, the Yellowlegged gull (Larus michahellis).Methods The data include the encounter histories of 5158 birds marked as fledglings between 1999 and 2004 at 14 different colonies in southern France and resighted over 10 years. Using a multi-event mark-recapture modeling framework, we use these data to estimate the probability of movement and survival, taking into account recapture heterogeneity and age. Results In accordance with previous studies, we find that young individuals have greater mobility than older individuals. However, the spatial extent of juvenile movements depends on natal colony location, with a strong difference in the proportion of sedentary individuals among colonies less than 50 km apart. Colony quality or local population dynamics may explain these differences. Indeed, young birds from colonies with strong juvenile survival probabilities (~ 0.75) appear to be more sedentary than those from colonies with low survival probabilities (~ 0.36).Conclusions This study shows the importance of studying individuals of different ages and from different colonies when trying to understand seabird movement strategies. Local breeding success and the availability of food resources may explain part of the among colony differences we observe and require explicit testing. We discuss our results with respect to the feedback loop that may occur between breeding success and mobility, and its potential implications for population demography and the dissemination of avian disease at different spatial scales

Association of human leukocyte antigen haplotypes with posttransplant lymphoproliferative disease after solid organ transplantation

Background. Posttransplant lymphoproliferative disease (PTLD) after solid organ transplantation (SOT) is commonly characterized by Epstein-Barr virus (EBV)-driven proliferation of recipient B cells due to impaired immune surveillance in the context of immunosuppression. Because EBV-specific T-cell responses are focused on the level of EBV antigen and epitope choice depending on the individual human leukocyte antigen (HLA) alleles, we hypothesized that certain HLA alleles or a distinct HLA haplotype may influence the risk of development of PTLD after SOT. Methods. A multicenter case-control study was performed comparing a group of 155 recipients after SOT with development of PTLD with a group of 1996 recipients after SOT without development of PTLD. Alleles, genotypes, and three locus haplotypes were compared of SOT recipients with and without PTLD. Results. The bivariate analysis showed that carrying HLA-A03 was negatively associated (odds ratio [OR] 0.61, confidence interval [CI] 0.40-0.92, P <0.02) whereas carrying of HLA-B 18 (OR 1.79, CI 1.18-2.73, P <0.006) and HLA-B21 (OR 2.08, CI 1.14-3.77, P <0.02) were positively associated with PTLD after SOT. HLA-DR analysis demonstrated a significant negative association between the expression of HLA-DR7 (OR 0.46, CI 0.28-0.78, P <0.004) and PTLD. Three locus haplotype analysis underlined the relevance of a dominant protective effect of HLA-DR7 expression concerning the risk of PTLD development. Conclusions. Our data suggest an influence of HLA variants on the risk of the development of PTLD. We hypothesize that HLA genes or non-HLA genes within the HLA loci confer a risk modification for the individual patient

Temozolomide Is Effective and Well Tolerated in Patients with Primary Vitreoretinal Lymphoma

International audienceNo abstract availabl