Insights into the structural dynamics of poly lactic-: Co -glycolic acid at terahertz frequencies

The mechanical properties of an amorphous copolymer are directly related to the dynamic processes occurring at the molecular level.</p

Exposure assessment methods for examining the role of non-chemical stressors in environmental health disparities

Increases in chronic diseases among children are cause for public health concern and action, particularly as children of color and low socioeconomic position are disproportionately impacted, with far-reaching consequences for health and well-being over the life-course. Environmental toxicants and non-chemical stressors have been linked with adverse health outcomes and disparities. Specifically, recent toxicological and epidemiological evidence suggests that chronic psychosocial stress may modify pollution effects on health. Thus, there is increasing interest in refined methods for assessing and incorporating non-chemical exposures, including social stressors, into environmental health research, towards identifying whether and how psychosocial stress interacts with chemical exposures to influence health and health disparities. The overall objective of this dissertation is to apply exposure science principles to develop and validate methods for non-chemical exposure assessment, toward examining differential susceptibility and disproportionate exposures in social-environmental epidemiology. To do so, I utilize a spatial approach to characterize intra-urban variation in and correlation among social stressors, socioeconomic position, and air pollution exposures across New York City. I present flexible GIS-based approaches for reformulating aggregate administrative indicators for global correlation analysis, accounting for spatial autocorrelation, and assessing perceived neighborhood geography. I assess multiple foci of the stress process paradigm using qualitative and quantitative methods, and evaluate the extent to which multiple components of social environment are implicated in psychosocial pathways, with specific attention to distinguishing socioeconomic and stress pathways. Complex interaction between air pollution and area-level deprivation effects on term birth weight suggested differential population susceptibility, and the need for mechanism-specific non-chemical exposure metrics. Spatially, ecologic indicators of social stressor exposures and air pollution were not consistently correlated with each other, or with indicators of socioeconomic position, and were not consistently associated with child asthma exacerbation rates. Community perceptions of important social stressors assessed through a qualitative process informed upon the design and implementation of a systematic survey to validate the resonance of ecologic stressor indicators against individual stress perception and mental health. Overall, these non-chemical exposure assessment methods enable characterization of complex confounding in urban environments, toward refining epidemiologic investigations of separate and combined effects of social and chemical exposures

Advancing predictions of protein stability in the solid state.

The β-relaxation associated with the sub-glass transition temperature (Tg,β) is attributed to fast, localised molecular motions which can occur below the primary glass transition temperature (Tg,α). Consistent with Tg,β being observed well-below storage temperatures, the β-relaxation associated motions have been hypothesised to influence protein stability in the solid state and could thus impact the quality of e.g. protein powders for inhalation or reconstitution and injection. Why then do distinct solid state protein formulations with similar aggregation profiles after drying and immediate reconstitution, display different profiles when reconstituted following prolonged storage? Is the value of Tg,β, associated with the β-relaxation process of the system, a reliable parameter for characterising the behaviour of proteins in the solid state? Bearing this in mind, in this work we further explore the different relaxation dynamics of glassy solid state monoclonal antibody formulations using terahertz time-domain spectroscopy and dynamical mechanical analysis. By conducting a 52 week stability study on a series of multi-component spray-dried formulations, an approach for characterising and analysing the solid state dynamics and how these relate to protein stability is outlined.EPSR

Social stressors and air pollution across New York City communities: a spatial approach for assessing correlations among multiple exposures

Background: Recent toxicological and epidemiological evidence suggests that chronic psychosocial stress may modify pollution effects on health. Thus, there is increasing interest in refined methods for assessing and incorporating non-chemical exposures, including social stressors, into environmental health research, towards identifying whether and how psychosocial stress interacts with chemical exposures to influence health and health disparities. We present a flexible, GIS-based approach for examining spatial patterns within and among a range of social stressors, and their spatial relationships with air pollution, across New York City, towards understanding their combined effects on health. Methods: We identified a wide suite of administrative indicators of community-level social stressors (2008–2010), and applied simultaneous autoregressive models and factor analysis to characterize spatial correlations among social stressors, and between social stressors and air pollutants, using New York City Community Air Survey (NYCCAS) data (2008-2009). Finally, we provide an exploratory ecologic analysis evaluating possible modification of the relationship between nitrogen dioxide (NO2) and childhood asthma Emergency Department (ED) visit rates by social stressors, to demonstrate how the methods used to assess stressor exposure (and/or consequent psychosocial stress) may alter model results. Results: Administrative indicators of a range of social stressors (e.g., high crime rate, residential crowding rate) were not consistently correlated (rho = - 0.44 to 0.89), nor were they consistently correlated with indicators of socioeconomic position (rho = - 0.54 to 0.89). Factor analysis using 26 stressor indicators suggested geographically distinct patterns of social stressors, characterized by three factors: violent crime and physical disorder, crowding and poor access to resources, and noise disruption and property crimes. In an exploratory ecologic analysis, these factors were differentially associated with area-average NO2 and childhood asthma ED visits. For example, only the ‘violent crime and disorder’ factor was significantly associated with asthma ED visits, and only the ‘crowding and resource access’ factor modified the association between area-level NO2 and asthma ED visits. Conclusions: This spatial approach enabled quantification of complex spatial patterning and confounding between chemical and non-chemical exposures, and can inform study design for epidemiological studies of separate and combined effects of multiple urban exposures. Electronic supplementary material The online version of this article (doi:10.1186/1476-069X-13-91) contains supplementary material, which is available to authorized users

Ambient ozone exposure and children's acute asthma in New York City: A case-crossover analysis Children s Environmental Health

Background: Childhood asthma morbidity has been associated with ambient ozone in case-crossover studies. Varying effects of ozone by child age and sex, however, have been less explored. Methods: This study evaluates associations between ozone exposure and asthma emergency department visits and hospitalizations among boys and girls aged 5-17 years in New York City for the 2005-2011 warm season period. Time-stratified case-crossover analysis was conducted and, for comparison, time-series analysis controlling for season, day-of-week, same-day and delayed effects of temperature and relative humidity were also performed. Results: We found associations between ambient ozone levels and childhood asthma emergency department visits and hospitalizations in New York City, although the relationships varied among boys and girls and by age group. For an increase of interquartile range (0.013 ppm) in ozone, there was a 2.9-8.4% increased risk for boys and 5.4-6.5% for girls in asthma emergency department visits; and 8.2% increased risk for girls in hospitalizations. Among girls, we observed stronger associations among older children (10-13 and 14-17 year age groups). We did not observe significant modification by age for boys. Boys exhibited a more prompt response (lag day 1) to ozone than did girls (lag day 3), but significant associations for girls were retained longer, through lag day 6. Conclusions: Our study indicates significant variance in associations between short-term ozone concentrations and asthma events by child sex and age. Differences in ozone response for boys and girls, before and after puberty, may point towards both social (gendered) and biological (sex-linked) sources of effect modification

Next generation strategy for tuning the thermoresponsive properties of micellar and hydrogel drug delivery vehicles using ionic liquids

Amongst the greatest challenges in developing injectable controlled thermoresponsive micellar and hydrogel drug delivery vehicles include tuning the cloud point (CP) and reducing the gelation temperature (Tgel), below 37 °C, without compromising stability and solubility. Here, a unique strategy is employed using ionic liquid (IL) matrices to produce stable micellar and hydrogel delivery vehicles of distinct thermoresponsive properties. Each formulation includes the in-house synthesised polymer OEGMA30020-b-BuMA22-b-DEGMA11 with FITC-IgG. Both micellar-IL and hydrogel-IL formulations exhibit enhanced stability following 120 days of storage under 4 °C compared to in phosphate buffered saline (PBS). Visual tests demonstrate that the CP of the micellar-IL carriers can be finely tuned (31- 46 °C). Rheology measurements show that hydrogel strength is significantly increased and Tgel is reduced, from 40 °C in PBS to 30 °C with IL. Finally, a unique stabilisation mechanism is proposed, triggered by the synergetic action of the excipients and IL in each syste

ABC block copolymer micelles driving the thermogelation:Scattering, imaging and spectroscopy

Thermoresponsive polymers have attracted much scientific attention due to their capacity for temperature-driven hydrogel formation. For biomedical applications, such as drug delivery, this transition should be tuned below body temperature to facilitate controlled and targeted drug release. We have recently developed a thermoresponsive polymer that forms gel at low concentrations (2 w/w%) in aqueous media and offers a cost-effective alternative to thermoresponsive systems currently being applied in clinics. This polymer is an ABC triblock terpolymer, where A, B, and C correspond to oligo(ethylene glycol) methyl ether methacrylate with average Mn 300 g mol−1 (OEGMA300), n-butyl methacrylate (BuMA), and di(ethylene glycol) methyl ether methacrylate (DEGMA). To investigate the self-assembly and the gelation mechanism in diluted solutions, we used small-angle neutron scattering (SANS) on 1 w/w% (below the gelation concentration) and 5 w/w% solutions (above the gelation concentration). As a comparison, we also investigated the solutions of the most studied thermoresponsive polymer, namely, Pluronic F127, an ABA triblock bipolymer made of ethylene glycol (A) and propylene glycol (B) blocks. SANS revealed that the in-house synthesised polymer forms elliptical cylinders, whose length increases significantly with temperature. In contrast, Pluronic F127 solutions form core-shell spherical micelles, which slightly elongate with temperature. Transmission electron microscopy images support the SANS findings, with tubular/worm structures being present. Variable-temperature circular dichroism (CD) and proton nuclear magnetic resonance (1H NMR) spectroscopy experiments reveal insights on the tacticity, structural changes, and molecular origin of the self-assembly

Social stressors and air pollution across New York City communities: A spatial approach for assessing correlations among multiple exposures

Background: Recent toxicological and epidemiological evidence suggests that chronic psychosocial stress may modify pollution effects on health. Thus, there is increasing interest in refined methods for assessing and incorporating non-chemical exposures, including social stressors, into environmental health research, towards identifying whether and how psychosocial stress interacts with chemical exposures to influence health and health disparities. We present a flexible, GIS-based approach for examining spatial patterns within and among a range of social stressors, and their spatial relationships with air pollution, across New York City, towards understanding their combined effects on health. Methods: We identified a wide suite of administrative indicators of community-level social stressors (2008-2010), and applied simultaneous autoregressive models and factor analysis to characterize spatial correlations among social stressors, and between social stressors and air pollutants, using New York City Community Air Survey (NYCCAS) data (2008-2009). Finally, we provide an exploratory ecologic analysis evaluating possible modification of the relationship between nitrogen dioxide (NO2) and childhood asthma Emergency Department (ED) visit rates by social stressors, to demonstrate how the methods used to assess stressor exposure (and/or consequent psychosocial stress) may alter model results. Results: Administrative indicators of a range of social stressors (e.g., high crime rate, residential crowding rate) were not consistently correlated (rho = - 0.44 to 0.89), nor were they consistently correlated with indicators of socioeconomic position (rho = - 0.54 to 0.89). Factor analysis using 26 stressor indicators suggested geographically distinct patterns of social stressors, characterized by three factors: violent crime and physical disorder, crowding and poor access to resources, and noise disruption and property crimes. In an exploratory ecologic analysis, these factors were differentially associated with area-Average NO2 and childhood asthma ED visits. For example, only the 'violent crime and disorder' factor was significantly associated with asthma ED visits, and only the 'crowding and resource access' factor modified the association between area-level NO2 and asthma ED visits. Conclusions: This spatial approach enabled quantification of complex spatial patterning and confounding between chemical and non-chemical exposures, and can inform study design for epidemiological studies of separate and combined effects of multiple urban exposures

Terahertz Spectroscopy: An investigation of the Structural Dynamics of Freeze-Dried Poly Lactic-co-glycolic Acid Microspheres

Biodegradable poly lactic-co-glycolic acid (PLGA) microspheres can be used to encapsulate peptide and offer a promising drug delivery vehicle. In this work we investigate the dynamics of PLGA microspheres prepared by freeze-drying and the molecular mobility at lower temperatures leading to the glass transition temperature, using temperature-variable terahertz time-domain spectroscopy (THz-TDS) experiments. The microspheres were prepared using a water-in-oil-in-water (w/o/w) double emulsion technique and subsequent freeze-drying of the samples. Physical characterisation was performed by morphology measurements, scanning electron microscopy, and helium pycnometry. The THz-TDS data show two distinct transition processes, $T_{\text{g},\beta}$ in the range of $167-219\,$K, associated with local motions, and $T_{\text{g},\alpha}$ in the range of $313-330\,$K associated with large-scale motions, for the microspheres examined. Using Fourier transform infrared spectroscopy measurements in the mid-infrared we were able to characterise the interactions between a model polypeptide, exendin-4, and the PLGA copolymer. We observe a relationship between the experimentally determined $T_{\text{g},\beta}$ and $T_{\text{g},\alpha}$ and free volume and microsphere dynamics.The authors acknowledge funding from AstraZeneca UK Limited (Medlmmune Limited) and the UK Engineering and Physical Sciences Research Council (EP/N022769/1). T.A.S. would like to thank the AJA-Karten Trust and the AIA-Kenneth Lindsay Trust for their financial support