Interplay of drug transporters P-glycoprotein (MDR1), MRP1, OATP1A2 and OATP1B3 in passage of maraviroc across human placenta

Special attention is required when pharmacological treatment is indicated for a pregnant woman. P-glycoprotein (MDR1) is a well-known transporter localized in the maternal blood-facing apical membrane of placental syncytiotrophoblast and is considered to play an important role in protecting the developing fetus. Maraviroc, a MDR1 substrate that is registered for treatment of HIV infection, shows a low toxicity profile, suggesting favorable tolerability also if administered to pregnant women. Nevertheless, there is only poor understanding to date regarding the extent to which it permeates across the placental barrier and what are the transport mechanisms involved. Endeavoring to clarify the passage of maraviroc across placenta, we used in this study the method of closed-circuit perfusion of maraviroc across human placental cotyledon. The data obtained confirmed slight involvement of MDR1, but they also suggest possible interaction with other transport system(s) working in the opposite direction from that of MDR1. Complementary in vitro studies, including cellular experiments on choriocarcinoma BeWo cells as well as transporter-overexpressing MDCKII and A431 cell lines and accumulation in placental fresh villous fragments, revealed maraviroc transport by MRP1, OATP1A2, and OATP1B3 transporters. Based on mRNA expression data in the placental tissue, isolated trophoblasts, and fetal endothelial cells, especially MRP1 and OATP1A2 seem to play a crucial role in cooperatively driving maraviroc into placental tissue. By the example of maraviroc, we show here the important interplay of transporters in placental drug handling and its possibility to overcome the MDR1-mediated efflux. © 2020 The Author

Primary care bonus payments and patient-reported access in urban Ontario: a cross-sectional study

BACKGROUND: Rurality strongly correlates with higher pay-for-performance access bonuses, despite higher emergency department use and fewer primary care services than in urban settings. We sought to evaluate the relation between patient-reported access to primary care and access bonus payments in urban settings. METHODS: We conducted a cross-sectional, secondary data analysis using Ontario survey and health administrative data from 2013 to 2017. We used administrative data to calculate annual access bonuses for eligible urban family physicians. We linked this payment data to adult (≥ 16 yr) patient data from the Health Care Experiences Survey to examine the relation between access bonus achievement (in quintiles of the proportion of bonus achieved, from lowest [Q1, reference category] to highest [Q5]) and 4 patient-reported access outcomes. The average survey response rate to the patient survey during the study period was 51%. We stratified urban geography into large, medium and small settings. In a multilevel regression model, we adjusted for patient-, physician- and practice-level covariates. We tested linear trends, adjusted for clustering, for each outcome. RESULTS: We linked 18 893 respondents to 3940 physicians in 414 bonus-eligible practices. Physicians in small urban settings earned the highest proportion of their maximum potential access bonuses. Access bonus achievement was positively associated with telephone access (Q2 odds ratio [OR] 1.18, 95% confidence interval [CI] 0.98-1.42; Q3 OR 1.34, 95% CI 1.10-1.63; Q4 OR 1.46, 95% CI 1.19-1.79; Q5 OR 1.87, 95% CI 1.50-2.33), after hours access (Q2 OR 1.26, 95% CI 1.09-1.47; Q3 OR 1.46, 95% CI 1.23-1.74; Q4 OR 1.77, 95% CI 1.46-2.15; Q5 OR 1.88, 95% CI 1.52-2.32), wait time for care (Q2 OR 1.01, 95% CI 0.85-1.20; Q3 OR 1.17, 95% CI 0.97-1.41; Q4 OR 1.27, 95% CI 1.05-1.55; Q5 OR 1.63, 95% CI 1.32-2.00) and timeliness (Q2 OR 1.29, 95% CI 0.98-1.69; Q3 OR 1.29, 95% CI 0.94-1.77; Q4 OR 1.58, 95% CI 1.16-2.13; Q5 OR 1.98, 95% CI 1.38-2.82). When stratified by geography, we observed several of these associations in large urban settings, but not in small urban settings. Trend tests were statistically significant for all 4 outcomes. INTERPRETATION: Although the access bonus correlated with access in larger urban settings, it did not in smaller settings, aligning with previous research questioning its utility in smaller geographies. The access bonus may benefit from a redesign that considers geography and patient experience

Road users rarely use explicit communication when interacting in today’s traffic: Implications for Automated Vehicles

To be successful, automated vehicles (AVs) need to be able to manoeuvre in mixed traffic in a way that will be accepted by road users, and maximises traffic safety and efficiency. A likely prerequisite for this success is for AVs to be able to communicate effectively with other road users in a complex traffic environment. The current study, conducted as part of the European project interACT, investigates the communication strategies used by drivers and pedestrians while crossing the road at six observed locations, across three European countries. In total, 701 road user interactions were observed and annotated, using an observation protocol developed for this purpose. The observation protocols identified 20 event categories, observed from the approaching vehicles/drivers and pedestrians. These included information about movement, looking behaviour, hand gestures, and signals used, as well as some demographic data. These observations illustrated that explicit communication techniques, such as honking, flashing headlights by drivers, or hand gestures by drivers and pedestrians, rarely occurred. This observation was consistent across sites. In addition, a follow-on questionnaire, administered to a sub-set of the observed pedestrians after crossing the road, found that when contemplating a crossing, pedestrians were more likely to use vehicle-based behaviour, rather than communication cues from the driver. Overall, the findings suggest that vehicle-based movement information such as yielding cues are more likely to be used by pedestrians while crossing the road, compared to explicit communication cues from drivers, although some cultural differences were observed. The implications of these findings are discussed with respect to design of suitable external interfaces and communication of intent by future automated vehicles

Combining PREM compilation and static scheduling for high-performance and predictable MPSoC execution

Many applications require both high performance and predictable timing. High-performance can be provided by COTS Multi-Core System on Chips (MPSoC), however, as cores in these systems share main memory, they are susceptible to interference from each other, which is a problem for timing predictability. We achieve predictability on multi-cores by employing the predictable execution model (PREM), which splits execution into a sequence of memory and compute phases, and schedules these such that only a single core is executing a memory phase at a time. We present a toolchain consisting of a compiler and a scheduling tool. Our compiler uses region and loop based analysis and performs tiling to transform application code into PREM-compliant binaries. In addition to enabling predictable execution, the compiler transformation optimizes accesses to the shared main memory. The scheduling tool uses a state-of-the-art heuristic algorithm and is able to schedule industrial-size instances. For smaller instances, we compare the results of the algorithm with optimal solutions found by solving an integer linear programming model. Furthermore, we solve the problem of scheduling execution on multiple cores while preventing interference of memory phases. We evaluate our toolchain on Advanced Driver Assistance System (ADAS) application workloads running on an NVIDIA Tegra X1 embedded system-on-chip (SoC). The results show that our approach maintains similar average performance to the original (unmodified) program code and execution, while reducing variance of completion times by a factor of 9 with the identified optimal solutions and by a factor of 5 with schedules generated by our heuristic scheduler

Influence of an oligodendroglial component on the survival of patients with anaplastic astrocytomas: A report of radiation therapy oncology group 83-02

Purpose : Seven percent of patients with high grade gliomas enrolled in RTOG 83-02 had mixed astrocytoma/oligodenroglial elements on central pathology review. It has often been assumed that the most aggressive histologic component of a tumor determines biologic behavior; however in this trial, the survival of patients who had mixed glioblastomas/oligodenrogliomas was significantly longer than that of patients with pure glioblastomas (GBM). We therefore evaluated the effect of an oligodendroglial component on the survival of patients who had anaplastic astrocytomas (AAF) treated in the same trial. Methods and Materials : One hundred nine patients who had AAF and 24 patients with mixed AAF/oligodendrogliomas (AAF/OL) were enrolled in a Phase I/II trial of randomized dose-escalation hyperfractioned radiotherapy plus BCNU. AAF/OL patients were older and more likely to have had more aggressive surgery than AAF patients. Other pretreatment characteristics were balanced between groups, as was assigned treatment. Results : The median survival time for AAF was 3.0 years versus 7.3 years for AAF/OL ( p = 0.019). In a multivariate analysis, adjusting for extent of surgical resection and age, an oligodendroglial component was an independent prognostic factor for survival. Conclusion : The results support the concept that AAFs with an oligodendroglial component have a better prognosis than pure AAF tumors, similar to the effect seen among patients with glioblastoma multiforme tumors. This better survival outcome should be taken into consideration in the design and stratification of future trials. Additionally, in contrast to patients with GBMs, patients who have AAF/OL have the potential for prolonged survival; therefore, late sequelae of treatment (both radiation and chemotherapy) must be weighed more heavily in the benefits to risks analysis