Developing air pollution concentration fields for health studies using multiple methods: Cross-comparison and evaluation.

Past air pollution epidemiological studies have used a wide range of methods to develop concentration fields for health analyses. The fields developed differ considerably among these methods. The reasons for these differences and comparisons of their strengths, as well as the limitations for estimating exposures, remains under-investigated. Here, we applied nine methods to develop fields of eight pollutants (carbon monoxide (CO), nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), fine particulate matter (PM2.5), and three speciated PM2.5 constituents including elemental carbon (EC), organic carbon (OC), and sulfate (SO4)) for the metropolitan Atlanta region for five years. The nine methods are Central Monitor (CM), Site Average (SA), Inverse Distance Weighting (IDW), Kriging (KRIG), Land Use Regression (LUR), satellite Aerosol Optical Depth (AOD), CMAQ model, CMAQ with kriging adjustment (CMAQ-KRIG), and CMAQ based data fusion (CMAQ-DF). Additionally, we applied an increasingly popular method, Random Forest (RF), and compared its results for NO2 and PM2.5 with other methods. For statistical evaluation, we focused our discussion on the temporal coefficient of determination, although other metrics are also calculated. Raw output from the CMAQ model contains modeling biases and errors, which are partially mitigated by fusing observational data in the CMAQ-KRIG and CMAQ-DF methods. Based on analyses that simulated model responses to more limited input data, the RF model is more robust and outperforms LUR for PM2.5. These results suggest RF may have potential in air pollution health studies, especially when limited measurement data are available. The RF method has several important weaknesses, including a relatively poor performance for NO2, diagnostic challenges, and computational intensiveness. The results of this study will help to improve our understanding of the strengths and weaknesses of different methods for estimating air pollutant exposures in epidemiological studies.

Long-term aircraft noise exposure and risk of hypertension in the Nurses' Health Studies.

BACKGROUND: Aircraft noise can affect populations living near airports. Chronic exposure to aircraft noise has been associated with cardiovascular disease, including hypertension. However, previous studies have been limited in their ability to characterize noise exposures over time and to adequately control for confounders. OBJECTIVES: The aim of this study was to examine the association between aircraft noise and incident hypertension in two cohorts of female nurses, using aircraft noise exposure estimates with high spatial resolution over a 20-year period. METHODS: We obtained contour maps of modeled aircraft noise levels over time for 90 U.S. airports and linked them with geocoded addresses of participants in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II) to assign noise exposure for 1994-2014 and 1995-2013, respectively. We used time-varying Cox proportional hazards models to estimate hypertension risk associated with time-varying noise exposure (dichotomized at 45 and 55 dB(A)), adjusting for fixed and time-varying confounders. Results from both cohorts were pooled via random effects meta-analysis. RESULTS: In meta-analyses of parsimonious and fully-adjusted models with aircraft noise dichotomized at 45 dB(A), hazard ratios (HR) for hypertension incidence were 1.04 (95% CI: 1.00, 1.07) and 1.03 (95% CI: 0.99, 1.07), respectively. When dichotomized at 55 dB(A), HRs were 1.10 (95% CI: 1.01, 1.19) and 1.07 (95% CI: 0.98, 1.15), respectively. After conducting fully-adjusted sensitivity analyses limited to years in which particulate matter (PM) was obtained, we observed similar findings. In NHS, the PM-unadjusted HR was 1.01 (95% CI: 0.90, 1.14) and PM-adjusted HR was 1.01 (95% CI: 0.89, 1.14); in NHS II, the PM-unadjusted HR was 1.08 (95% CI: 0.96, 1.22) and the PM-adjusted HR was 1.08 (95% CI: 0.95, 1.21). Overall, in these cohorts, we found marginally suggestive evidence of a positive association between aircraft noise exposure and hypertension.

Review and analysis of personal-ambient ozone measurements.

Ambient ozone measurements are often used as surrogates for personal exposures. Due to the limited number of central ozone monitors and varying personal behavioral patterns, some level of variability between ambient and personal exposures is expected. Low-cost sensors and different ways to capture personal activity patterns are being developed as an effort to improve the accuracy of exposure assessment. However, it is still most common to use the traditional approach of using unadjusted ambient concentrations as surrogates for personal exposures. To our knowledge, there has not been a meta-analysis that summarizes the findings from studies that investigated the differences between personal and ambient ozone. We conducted a literature search in PubMed and Science Direct for peer-reviewed studies reporting at least one of the following in a numeric format: 1) personal-ambient measurements, 2) personal-ambient slopes, or 3) personal-ambient correlations to identify and summarize existing studies that investigated personal and ambient ozone concentrations. Twenty-two articles met inclusion criteria and were included in our review. Ambient concentrations almost always overestimated personal exposures. A meta-analysis of slopes showed an overall personal-ambient slope of 0.21 (95% CI: 0.15, 0.27) with high heterogeneity (97%) across studies. The correlations between personal and ambient ozone varied dramatically across subjects from a strong positive (0.77) to a moderate negative correlation (-0.43). Our study found that ambient measurements are not accurate representations of personal exposure, while the magnitude of exposure measurement error varied across studies. Different sources of ozone and how they contribute to true exposure levels for individuals in complementary ways need to be better addressed. The effort to better understand the impact of traditional exposure assessment on the risk estimates must be emphasized along with efforts to improve the current exposure assessment approaches to provide context for interpreting the results from ozone epidemiological studies. Implications: The traditional approach of using ambient ozone measurements as surrogates for personal exposures is likely to result in exposure misclassification, which is a well-recognized source of bias in epidemiological studies. There are efforts to characterize the differences between ambient and personal ozone measurements, though, to our knowledge, there has not been a meta-analysis that summarizes the findings of different studies. Better understanding of the pattern and magnitude of exposure error for ambient and personal ozone can provide directions for future studies and context for interpreting the results from ozone epidemiological studies.

Leader cell PLCγ1 activation during keratinocyte collective migration is induced by EGFR localization and clustering.

Re-epithelialization is a critical step in wound healing and results from the collective migration of keratinocytes. Previous work demonstrated that immobilized, but not soluble, epidermal growth factor (EGF) resulted in leader cell-specific activation of phospholipase C gamma 1 (PLCγ1) in HaCaT keratinocytes, and that this PLCγ1 activation was necessary to drive persistent cell migration. To determine the mechanism responsible for wound edge-localized PLCγ1 activation, we examined differences in cell area, cell-cell interactions, and EGF receptor (EGFR) localization between wound edge and bulk cells treated with vehicle, soluble EGF, or immobilized EGF. Our results support a multistep mechanism where EGFR translocation from the lateral membrane to the basolateral/basal membrane allows clustering in response to immobilized EGF. This analysis of factors regulating PLCγ1 activation is a crucial step toward developing therapies or wound dressings capable of modulating this signal and, consequently, cell migration.

Immobilized epidermal growth factor stimulates persistent, directed keratinocyte migration via activation of PLCγ1.

Epidermal growth factor (EGF) is a critical element in dermal repair, but EGF-containing wound dressings have not been successful clinically. However, these dressings have delivered only soluble EGF, and the native environment provides both soluble and matrix-bound EGF. To address our hypothesis that tethered EGF can stimulate cell behaviors not achievable with soluble EGF, we examined single-cell movement and signaling in human immortalized HaCaT keratinocytes treated with soluble or immobilized EGF. Although both EGF treatments increased collective sheet displacement and individual cell speed, only cells treated with immobilized EGF exhibited directed migration, as well as 2-fold greater persistence compared with soluble EGF. Immunofluorescence showed altered EGF receptor (EGFR) trafficking, where EGFR remained membrane-localized in the immobilized EGF condition. Cells treated with soluble EGF demonstrated higher phosphorylated ERK1/2, and cells on immobilized EGF exhibited higher pPLCγ1, which was localized at the leading edge. Treatment with U0126 inhibited migration in both conditions, demonstrating that ERK1/2 activity was necessary but not responsible for the observed differences. In contrast, PLCγ1 inhibition with U73122 significantly decreased persistence on immobilized EGF. Combined, these results suggest that immobilized EGF increases collective keratinocyte displacement via an increase in single-cell migration persistence resulting from altered EGFR trafficking and PLCγ1 activation.-Kim, C. S., Mitchell, I. P., Desotell, A. W., Kreeger, P. K., Masters, K. S. Immobilized epidermal growth factor stimulates persistent, directed keratinocyte migration via activation of PLCγ1.

Awareness, Interest, and Preferences of Primary Care Providers in Using Point-of-Care Cancer Screening Technology.

Well-developed point-of-care (POC) cancer screening tools have the potential to provide better cancer care to patients in both developed and developing countries. However, new medical technology will not be adopted by medical providers unless it addresses a population's existing needs and end-users' preferences. The goals of our study were to assess primary care providers' level of awareness, interest, and preferences in using POC cancer screening technology in their practice and to provide guidelines to biomedical engineers for future POC technology development. A total of 350 primary care providers completed a one-time self-administered online survey, which took approximately 10 minutes to complete. A $50 Amazon gift card was given as an honorarium for the first 100 respondents to encourage participation. The description of POC cancer screening technology was provided in the beginning of the survey to ensure all participants had a basic understanding of what constitutes POC technology. More than half of the participants (57%) stated that they heard of the term "POC technology" for the first time when they took the survey. However, almost all of the participants (97%) stated they were either "very interested" (68%) or "somewhat interested" (29%) in using POC cancer screening technology in their practice. Demographic characteristics such as the length of being in the practice of medicine, the percentage of patients on Medicaid, and the average number of patients per day were not shown to be associated with the level of interest in using POC. These data show that there is a great interest in POC cancer screening technology utilization among this population of primary care providers and vast room for future investigations to further understand the interest and preferences in using POC cancer technology in practice. Ensuring that the benefits of new technology outweigh the costs will maximize the likelihood it will be used by medical providers and patients.

Efficient differentiation of steroidogenic and germ-like cells from epigenetically-related iPSCs derived from ovarian granulosa cells.

To explore restoration of ovarian function using epigenetically-related, induced pluripotent stem cells (iPSCs), we functionally evaluated the epigenetic memory of novel iPSC lines, derived from mouse and human ovarian granulosa cells (GCs) using c-Myc, Klf4, Sox2 and Oct4 retroviral vectors. The stem cell identity of the mouse and human GC-derived iPSCs (mGriPSCs, hGriPSCs) was verified by demonstrating embryonic stem cell (ESC) antigen expression using immunocytochemistry and RT-PCR analysis, as well as formation of embryoid bodies (EBs) and teratomas that are capable of differentiating into cells from all three germ layers. GriPSCs' gene expression profiles associate more closely with those of ESCs than of the originating GCs as demonstrated by genome-wide analysis of mRNA and microRNA. A comparative analysis of EBs generated from three different mouse cell lines (mGriPSCs; fibroblast-derived iPSC, mFiPSCs; G4 embryonic stem cells, G4 mESCs) revealed that differentiated mGriPSC-EBs synthesize 10-fold more estradiol (E2) than either differentiated FiPSC- or mESC-EBs under identical culture conditions. By contrast, mESC-EBs primarily synthesize progesterone (P4) and FiPSC-EBs produce neither E2 nor P4. Differentiated mGriPSC-EBs also express ovarian markers (AMHR, FSHR, Cyp19a1, ER and Inha) as well as markers of early gametogenesis (Mvh, Dazl, Gdf9, Boule and Zp1) more frequently than EBs of the other cell lines. These results provide evidence of preferential homotypic differentiation of mGriPSCs into ovarian cell types. Collectively, our data support the hypothesis that generating iPSCs from the desired tissue type may prove advantageous due to the iPSCs' epigenetic memory.