Environmental exposures associated with early childhood recurrent wheezing in the mother and child in the environment birth cohort: a time-to-event study.

BACKGROUND: Antenatal factors and environmental exposures contribute to recurrent wheezing in early childhood. AIM: To identify antenatal and environmental factors associated with recurrent wheezing in children from birth to 48 months in the mother and child in the environment cohort, using time-to-event analysis. METHOD: Maternal interviews were administered during pregnancy and postnatally and children were followed up from birth to 48 months (May 2013-October 2019). Hybrid land-use regression and dispersion modelling described residential antenatal exposure to nitrogen dioxide (NO2) and particulate matter of 2.5 µm diameter (PM2.5). Wheezing status was assessed by a clinician. The Kaplan-Meier hazard function and Cox-proportional hazard models provided estimates of risk, adjusting for exposure to environmental tobacco smoke (ETS), maternal smoking, biomass fuel use and indoor environmental factors. RESULTS: Among 520 mother-child pairs, 85 (16%) children, had a single wheeze episode and 57 (11%) had recurrent wheeze. Time to recurrent wheeze (42.9 months) and single wheeze (37.8 months) among children exposed to biomass cooking fuels was significantly shorter compared with children with mothers using electricity (45.9 and 38.9 months, respectively (p=0.03)). Children with mothers exposed to antenatal ETS were 3.8 times more likely to have had recurrent wheeze compared with those not exposed (adjusted HR 3.8, 95% CI 1.3 to 10.7). Mean birth month NO2 was significantly higher among the recurrent wheeze category compared with those without wheeze. NO2 and PM2.5 were associated with a 2%-4% adjusted increased wheezing risk. CONCLUSION: Control of exposure to ETS and biomass fuels in the antenatal period is likely to delay the onset of recurrent wheeze in children from birth to 48 months.

Randomized phase II trial of farletuzumab plus chemotherapy versus placebo plus chemotherapy in low CA-125 platinum-sensitive ovarian cancer.

OBJECTIVE: The primary purpose of this study was to determine if farletuzumab, an antifolate receptor-α monoclonal antibody, improved progression-free survival (PFS) versus placebo when added to standard chemotherapy regimens in patients with platinum-sensitive recurrent ovarian cancer (OC) in first relapse (platinum-free interval: 6-36 months) with low cancer antigen 125 (CA-125) levels. METHODS: Eligibility included CA-125 ≤ 3 x upper limit of normal (ULN, 105 U/mL), high-grade serous, platinum-sensitive recurrent OC, previous treatment with debulking surgery, and first-line platinum-based chemotherapy with 1st recurrence between 6 and 36 months since frontline platinum-based treatment. Patients received investigator's choice of either carboplatin (CARBO)/paclitaxel (PTX) every 3 weeks or CARBO/pegylated liposomal doxorubicin (PLD) every 4 weeks x6 cycles in combination with either farletuzumab [5 mg/kg weekly] or placebo randomized in a 2:1 ratio. Maintenance treatment with farletuzumab (5 mg/kg weekly) or placebo was given until disease progression or intolerance. RESULTS: 214 patients were randomly assigned to farletuzumab+chemotherapy (142 patients) versus placebo+chemotherapy (72 patients). The primary efficacy endpoint, PFS, was not significantly different between treatment groups (1-sided α = 0.10; p-value = 0.25; hazard ratio [HR] = 0.89, 80% confidence interval [CI]: 0.71, 1.11), a median of 11.7 months (95% CI: 10.2, 13.6) versus 10.8 months (95% CI: 9.5, 13.2) for farletuzumab+chemotherapy and placebo+chemotherapy, respectively. No new safety concerns were identified with the combination of farletuzumab+chemotherapy. CONCLUSIONS: Adding farletuzumab to standard chemotherapy does not improve PFS in patients with OC who were platinum-sensitive in first relapse with low CA-125 levels. Folate receptor-α expression was not measured in this study. (Clinical Trial Registry NCT02289950).

A hybrid air pollution / land use regression model for predicting air pollution concentrations in Durban, South Africa.

The objective of this paper was to incorporate source-meteorological interaction information from two commonly employed atmospheric dispersion models into the land use regression technique for predicting ambient nitrogen dioxide (NO2), sulphur dioxide (SO2), and particulate matter (PM10). The study was undertaken across two regions in Durban, South Africa, one with a high industrial profile and a nearby harbour, and the other with a primarily commercial and residential profile. Multiple hybrid models were developed by integrating air pollution dispersion modelling predictions for source specific NO2, SO2, and PM10 concentrations into LUR models following the European Study of Cohorts for Air Pollution Effects (ESCAPE) methodology to characterise exposure, in Durban. Industrial point sources, ship emissions, domestic fuel burning, and vehicle emissions were key emission sources. Standard linear regression was used to develop annual, summer and winter hybrid models to predict air pollutant concentrations. Higher levels of NO2 and SO2 were predicted in south Durban as compared to north Durban as these are industrial related pollutants. Slightly higher levels of PM10 were predicted in north Durban as compared to south Durban and can be attributed to either traffic, bush burning or domestic fuel burning. The hybrid NO2 models for annual, summer and winter explained 60%, 58% and 63%, respectively, of the variance with traffic, population and harbour being identified as important predictors. The SO2 models were less robust with lower R2 annual (44%), summer (53%) and winter (46%), in which industrial and traffic variables emerged as important predictors. The R2 for PM10 models ranged from 80% to 85% with population and urban land use type emerging as predictor variables.

Harbor and Intra-City Drivers of Air Pollution: Findings from a Land Use Regression Model, Durban, South Africa.

Multiple land use regression models (LUR) were developed for different air pollutants to characterize exposure, in the Durban metropolitan area, South Africa. Based on the European Study of Cohorts for Air Pollution Effects (ESCAPE) methodology, concentrations of particulate matter (PM10 and PM2.5), sulphur dioxide (SO2), and nitrogen dioxide (NO2) were measured over a 1-year period, at 41 sites, with Ogawa Badges and 21 sites with PM Monitors. Sampling was undertaken in two regions of the city of Durban, South Africa, one with high levels of heavy industry as well as a harbor, and the other small-scale business activity. Air pollution concentrations showed a clear seasonal trend with higher concentrations being measured during winter (25.8, 4.2, 50.4, and 20.9 µg/m3 for NO2, SO2, PM10, and PM2.5, respectively) as compared to summer (10.5, 2.8, 20.5, and 8.5 µg/m3 for NO2, SO2, PM10, and PM2.5, respectively). Furthermore, higher levels of NO2 and SO2 were measured in south Durban as compared to north Durban as these are industrial related pollutants, while higher levels of PM were measured in north Durban as compared to south Durban and can be attributed to either traffic or domestic fuel burning. The LUR NO2 models for annual, summer, and winter explained 56%, 41%, and 63% of the variance with elevation, traffic, population, and Harbor being identified as important predictors. The SO2 models were less robust with lower R2 annual (37%), summer (46%), and winter (46%) with industrial and traffic variables being important predictors. The R2 for PM10 models ranged from 52% to 80% while for PM2.5 models this range was 61-76% with traffic, elevation, population, and urban land use type emerging as predictor variables. While these results demonstrate the influence of industrial and traffic emissions on air pollution concentrations, our study highlighted the importance of a Harbor variable, which may serve as a proxy for NO2 concentrations suggesting the presence of not only ship emissions, but also other sources such as heavy duty motor vehicles associated with the port activities.

Land use regression modelling estimating nitrogen oxides exposure in industrial south Durban, South Africa.

BACKGROUND: The South Durban (SD) area of Durban, South Africa, has a history of air pollution issues due to the juxtaposition of low-income communities with industrial areas. This study used measurements of oxides of nitrogen (NOx) to develop a land use regression (LUR) model to explain the spatial variation of air pollution concentrations in this area. METHODS: Ambient NOx was measured over two two-week sampling periods at 32 sites using Ogawa badges. Following the ESCAPE approach, an annual adjusted average was calculated for these results and regressed against pre-selected geographic predictor variables in a multivariate regression model. The LUR model was then applied to predict the NOx exposure of a sample of pregnant women living in South Durban. RESULTS: Measured NOx levels ranged from 22.3-50.9µg/m3 with a median of 36µg/m3. The model developed accounts for 73% of the variance in ambient NOx measurements using three input variables (length of minor roads within a 1000m radius, length of major roads within a 300m radius, and area of open space within a 1000m radius). Model cross validation yielded a R2 of 0.59. Subsequent participant exposure estimates indicated exposure to ambient NOx ranged from 19.9-53.2µg/m3, with a mean of 39µg/m3. DISCUSSION AND CONCLUSION: This is the first study to develop a land use regression model that predicts ambient concentrations of NOx in a South African context. The findings of this study indicate that the participants in the South Durban are exposed to high levels of NOx that can be attributed mainly to traffic.

Pharmacokinetic comparison of two nicotine transdermal systems, a 21-mg/24-hour patch and a 25-mg/16-hour patch: a randomized, open-label, single-dose, two-way crossover study in adult smokers.

BACKGROUND: A comparison of the 21-mg NiQuitin patch with other marketed nicotine patches reported significant differences in pharmacokinetic profiles, even among patches of the identical labeled dose strength. The 25-mg Nicorette Invisi patch became available in the United Kingdom at the end of 2008. No published studies have directly compared the pharmacokinetic profile of this new patch with that of the 21-mg NiQuitin patch. OBJECTIVES: This study was conducted to compare the single-dose pharmacokinetics of the 21-mg/24-hour patch and the 25-mg/16-hour patch. To determine whether any pharmacokinetic differences might be related to differences in wear time, a post hoc exploratory analysis evaluated the nicotine delivery profiles of the patches under the assumption that the 21-mg patch was removed after 16 rather than 24 hours. METHODS: This was a single-center, randomized, open-label, single-dose, 2-way crossover study in healthy adults who smoked >10 cigarettes per day in the 6 months before the study. Eligible subjects were housed at the study center for 2 baseline and 2 treatment sessions; no smoking was permitted during the baseline or treatment sessions. Subjects were allocated to receive either the 21-mg patch (removed after 24 hours) or the 25-mg patch (removed after 16 hours) during the first treatment session, after which they crossed over to the alternative sequence in the second treatment session. Blood samples were obtained at predetermined time points before and after patch application. The primary pharmacokinetic parameter was the AUC(0-infinity), an indication of total nicotine exposure. Secondary pharmacokinetic parameters included AUC(0-t), C(max), and T(max). Post hoc exploratory parameters were the AUC(0-16) and the AUC(0-infinity) assuming a 16-hour application time for the 21-mg patch. The differences in AUC(0-infinity), AUC(0-t), Cmax, AUC(0-16), and AUC(0-infinity) assuming a 16-hour application time for the 21-mg patch were considered significant if the lower limit of the 90% CI for the geometric mean ratio (21 mg:25 mg) was >100%. T(max) values were compared using a signed-rank test. Adverse events were elicited using a standard open-ended question on each day of confinement; spontaneously reported events were also captured. The topical effects of the patch (erythema; edema; extent of erythema/papules/pustules; self-reported pruritus) were assessed by study staff before patch application and 1 and 8 hours after patch application using a 4-point rating scale; any topical effects were recorded as adverse events. RESULTS: Fifty otherwise healthy smokers (29 men, 21 women) were enrolled; 47 (94%) were white. Their mean (SD) age was 31.5 (9.57) years (range, 20-53 years), mean weight was 70.24 (9.56) kg (range, 51.0-95.9 kg), and mean height was 173.0 (8.02) cm (range, 156-194 cm). Subjects reported smoking between 11 and 40 cigarettes per day before the study. The AUC(0-infinity) was significantly higher for the 21-mg patch worn for 24 hours than for the 25-mg patch worn for 16 hours (382.36 vs 243.69 ng/mL . h, respectively; geometric mean ratio: 156.90%; 90% CI, 148.10%-166.23%; P < 0.001). T(max) was reached significantly sooner with the 21-mg patch than with the 25-mg patch (6.0 vs 12.0 hours; P < 0.001). C(max) was significantly higher for the 21-mg patch compared with the 25-mg patch (18.34 vs 16.56 ng/mL; geometric mean ratio: 110.72%; 90% CI, 104.82%-116.94%; P < 0.01). The exploratory analyses suggested that the 21-mg patch applied for 16 hours may provide greater total nicotine exposure than the 25-mg patch applied for 16 hours. Although most subjects reported adverse events (75.0% with the 21-mg patch, 89.8% with the 25-mg patch), the majority of these events were mild. CONCLUSIONS: In this single-dose study in adult smokers, the 21-mg patch was associated with significantly greater nicotine exposure compared with the 25-mg patch. The 21-mg patch provided a maximal nicotine concentration faster than did the 25-mg patch.