Search

Introduction: Nirogacestat is a targeted gamma secretase inhibitor approved in the United States for adults with progressing desmoid tumors. In the phase 3 DeFi study (NCT03785964) of nirogacestat, ovarian toxicity (OT) was identified as a safety signal among females of reproductive potential (FORP). This analysis further describes the incidence, presentation, and resolution of OT. Methods: Patients were randomized to twice‐daily oral nirogacestat (150 mg) or placebo, taken in continuous 28‐day cycles. Investigator‐identified OT in FORP was based on abnormal reproductive hormone values or perimenopausal symptoms (or both). Adverse event follow‐up was conducted to assess OT resolution. Post hoc analyses included return of menstruation and return of follicle‐stimulating hormone (FSH) to within normal limits (WNL) (≤20.4 mIU/mL). Results: Of 92 randomized females, 73 in the safety population were FORP (n = 36 nirogacestat, n = 37 placebo). OT was identified in 75% (27 of 36) receiving nirogacestat and 0% (0 of 37) receiving placebo. As of October 24, 2022, investigators reported OT resolution in 78% (21 of 27) of patients, with median OT duration of 19.1 weeks. Off‐treatment resolution was reported in all 11 patients (100%) who stopped nirogacestat treatment; of these, all nine with available menstruation information experienced return of menstruation and eight had FSH WNL at last reported assessment. Resolution was reported in 10 of 14 (71%) while on nirogacestat; of these, all 10 experienced return of menstruation and seven had FSH WNL. Two patients were lost to follow‐up. Conclusion: Most FORP treated with nirogacestat experienced OT, with the majority resolving, including all who stopped treatment, suggesting that OT is transient. In the phase 3 DeFi study of nirogacestat, a targeted gamma secretase inhibitor approved in the United States for adults with progressing desmoid tumors, ovarian toxicity was identified as a safety signal in most females of reproductive potential. The majority (78%) of ovarian toxicity events resolved, including in 100% of patients who stopped nirogacestat for any reason, suggesting that ovarian toxicity with nirogacestat is transient. [ABSTRACT FROM AUTHOR]

We evaluated the uncertainty associated with secondary pollutants formation due to different chemical mechanisms in photochemical modelling. The CMAQ modelling system was utilized in conjunction with CB6R3, SAPRC07, and RACM2 chemical mechanisms and compared the concentrations of various chemical species, including ozone (O3) and particulate matter (PM2.5). Using datasets from ambient monitoring stations, we assessed the performance of each of the mechanism in summer and winter. The concentrations of various chemical species predicted by the three mechanisms varied significantly. The differences are more evident in summer than in winter for most of the species, except for hydrogen peroxide (H2O2), methyl hydroperoxide (MEPX), and Secondary Organic Aerosol—Anthropogenic. We observed that the summer daytime O3 predictions showed reasonable peaks at the three air quality monitoring sites, but the nighttime values under-predicted for all three mechanisms. In the winter, all three mechanisms tend to under-predict O3. Differences in the mean O3 values (bias) at the different sites, for the different seasons, are consistent with corrections made to previous modelling studies that modified KZMIN. PM2.5 predictions with RACM2 were slightly better. The dominant PM2.5 species in summer were sulfate and SOA-Bio, which may be attributed to non-mobile sources in the region, while NO3 became dominant in winter due to more favorable conditions for forming this species, including lower temperatures and an elevated NH4 to SO4 ratio. We concluded that the differences in O3 and PM2.5 predictions between the three mechanisms are significant, implying that when developing strategic and management actions are based on modelling, the most appropriate mechanism should be considered. [ABSTRACT FROM AUTHOR]

Abstract: We conducted four source apportionment simulations using the Community Multiscale Air Quality (CMAQ) photochemical grid modelling system in order to investigate and assess the relative importance of specific emissions sources and/or geographic regions on ambient ozone and PM air quality in the Alberta Oil Sands Region (AOSR). Local point and area sources, medium range transport of mobile sources and biogenic emissions were examined. The elimination of emissions from local stationary point sources reduced 8-h ozone concentrations and greatly reduces the PM2.5 concentrations in AOSR; similar results are seen in the local area source zero-out simulations but with less ozone and PM2.5 reductions than seen in the local point source zero-out run. Although the mobile source medium-range transport reduced 8-h ozone concentrations in the urban plume from Edmonton that results in some ozone and PM2.5 concentration reductions in the southern part of the AOSR, it has little effect on the elevated ozone and PM2.5 concentrations in the oil sands development area of the AOSR where the highest ozone and PM2.5 concentrations are estimated. The elimination of all anthropogenic emissions in Alberta so that only biogenic emissions remained resulted in large reductions in 8-h ozone concentrations in the AOSR, with the highest remaining ozone in the 50–52ppb range occurring south of Fort McMurray; very low PM2.5 concentrations are also estimated across Alberta, including the AOSR, when anthropogenic emissions are eliminated in Alberta. [Copyright &y& Elsevier]

Abstract: The Community Multiscale Air Quality (CMAQ) and the Sparse Matrix Operator Kernel Emissions (SMOKE) modeling systems were used to simulate emissions and air quality in North Eastern Alberta where a rapid rise in oil sands development has caused air quality concerns over the last decade. The models were run on a 36/12/4 km domain for the four month period of May through August 2002. A model performance evaluation was conducted by comparing the CMAQ model estimates against ambient air quality measurements. In the Alberta oil sands region, the model tended to achieve or nearly achieve ozone model performance goals, albeit with an underestimation bias. The magnitudes of the observed PM2.5 concentrations were matched by the modeling system, except when the observed PM2.5 concentrations were influenced by emissions from forest fires in which case the model underestimated the observed PM2.5 concentrations. The CMAQ-estimated 4th highest daily maximum 8-hour ozone concentrations in the oil sands region were below the 65 ppb Canada Wide Standard (CWS) as well as the 58 ppb Alberta Management Plan Trigger Level. The highest estimated ozone concentrations occurred near the oil sands development area just north of Fort McMurray with values approaching, but below, the 58 ppb Management Plan Trigger Level; estimated ozone concentrations are much lower in the farther northern portions of the oil sands region. The acute (i.e., maximum 3-day value) SUM60 vegetative ozone exposure metric was mostly less than 100 ppb h, which is below the threshold of concern for crops. However, just north of Fort McMurray there were small areas where the acute SUM60 metric exceeded the 500–700 ppb h threshold of concern for crops with maximum values in plumes from sources in the oil sands mine area of ∼900 ppb h. The maximum chronic (three-month average) SUM60 ozone exposure metric was below the thresholds of concern. The CMAQ-estimated maximum 98th percentile 24-hour average PM2.5 concentration occurs in the mine area north of Fort McMurray and was below the CWS threshold (30 μg m−3), however it was above the Alberta Management Plan Trigger Level (20 μg m−3). The estimated 98th percentile 24- hour average PM2.5 concentrations were mostly in the 2–6 μg m−3 range with regions of higher PM2.5 concentrations predicted just north of Fort McMurray in the oil sands development region. [Copyright &y& Elsevier]

Background: A university education is becoming ever-more important in preparing for employment in the knowledge-driven economy. Yet, many university students are not able to complete their degrees because they experience mental health problems during the course of their higher education. Despite the growing numbers of students seeking help, there is limited knowledge about the issues that these students face., Objective: The purpose of this study was to understand the range of individual, interpersonal, and environmental factors that affect the lives of university students living with mental health problems., Methods: The study was based at a large public university in Canada. Semi-structured interviews were conducted with 19 students with self-identified mental health problems. Their narratives were analyzed using grounded theory methods and a model was developed which drew upon social-ecological theory., Results: Findings depict student experiences as a function of the self (individual factors), the social (interpersonal factors) and the school (environmental factors) and their interrelations., Conclusions: Interventions must be designed to address all three of these areas and their interrelations. The model can be used to guide universities in designing interventions; however, a fourth level that incorporates a university policy that values and supports student mental health, should be included.