Comparison of solubility profiles for pioneer and generic monensin premixes in biorelevant simulated intestinal fluid based on shake flask extractions.

In the United States, a generic Type A medicated article product can gain the FDA approval by demonstrating bioequivalence (BE) to the pioneer product by successfully conducting a blood level, pharmacodynamic, or clinical BE study. A biowaiver can be granted based on several criteria, assuming the dissolution of the test and reference products represents the only factor influencing the relative bioavailability of both products. Monensin is practically insoluble in H2O per the USP definition. Previously published data from a comparison study of monensin dissolution profiles from the pioneer product and four generic products using biorelevant media showed that generic monensin products demonstrated different dissolution profiles to the pioneer product in these USP biorelevant rumen media. This follow-up study compared the solubility profiles in simulated intestinal fluid (cFaSSIF, pH 7.5) for the pioneer product and four generic products. The generic monensin products demonstrated different in vitro dissolution profiles to the pioneer product in biorelevant media. The differences demonstrated in solubility and dissolution profiles are of concern regarding the potential efficacy of generic monensin in cattle. There are also additional concerns for the potential development of Eimeria resistance in cattle receiving a sub-therapeutic dose of monensin from a less soluble generic product.

A dependent Bayesian Dirichlet process model for source apportionment of particle number size distribution.

The relationship between particle exposure and health risks has been well established in recent years. Particulate matter (PM) is made up of different components coming from several sources, which might have different level of toxicity. Hence, identifying these sources is an important task in order to implement effective policies to improve air quality and population health. The problem of identifying sources of particulate pollution has already been studied in the literature. However, current methods require an a priori specification of the number of sources and do not include information on covariates in the source allocations. Here, we propose a novel Bayesian nonparametric approach to overcome these limitations. In particular, we model source contribution using a Dirichlet process as a prior for source profiles, which allows us to estimate the number of components that contribute to particle concentration rather than fixing this number beforehand. To better characterize them we also include meteorological variables (wind speed and direction) as covariates within the allocation process via a flexible Gaussian kernel. We apply the model to apportion particle number size distribution measured near London Gatwick Airport (UK) in 2019. When analyzing this data, we are able to identify the most common PM sources, as well as new sources that have not been identified with the commonly used methods.

The formation of a quadruple star system with wide separation.

The initial multiplicity of stellar systems is highly uncertain. A number of mechanisms have been proposed to explain the origin of binary and multiple star systems, including core fragmentation, disk fragmentation and stellar capture. Observations show that protostellar and pre-main-sequence multiplicity is higher than the multiplicity found in field stars, which suggests that dynamical interactions occur early, splitting up multiple systems and modifying the initial stellar separations. Without direct, high-resolution observations of forming systems, however, it is difficult to determine the true initial multiplicity and the dominant binary formation mechanism. Here we report observations of a wide-separation (greater than 1,000 astronomical units) quadruple system composed of a young protostar and three gravitationally bound dense gas condensations. These condensations are the result of fragmentation of dense gas filaments, and each condensation is expected to form a star on a timescale of 40,000 years. We determine that the closest pair will form a bound binary, while the quadruple stellar system itself is bound but unstable on timescales of 500,000 years (comparable to the lifetime of the embedded protostellar phase). These observations suggest that filament fragmentation on length scales of about 5,000 astronomical units offers a viable pathway to the formation of multiple systems.

Investigation of monensin Type A medicated article dissolution profiles in biorelevant media.

In the United States, a generic Type A medicated article (premix) product can gain government approval by demonstrating in vivo bioequivalence (BE) to the pioneer product in a blood level, pharmacodynamic, or clinical BE study. A biowaiver can be granted based on several criteria including solubility or a dose adjusted method. Monensin is practically insoluble in H2 O per the USP definition. A comparison was conducted of monensin dissolution profiles from the pioneer product and four generic products using biorelevant media. Dissolution profiles were obtained in both Bovine Simulated Rumen Fluids - High Forage and High Grain diets. Data from twelve vessels (6 vessels per dissolution run × 2) were collected across 8 hrs for each lot and media. Data are reported as % dissolved, based upon the corresponding lot potency (mg/g). With demonstrated acceptable intra-lot variability, data were analyzed using f1 (difference factor) and f2 (similarity factor) procedures. The generic monensin products did not demonstrate similar in vitro dissolution profiles to the pioneer product in these USP biorelevant media. Differences in physical parameters (particle size, flow characteristics, and physical composition) were observed between the pioneer and generic products, but these differences had no apparent impact on biorelevant dissolution.

A chronology of global air quality.

Air pollution has been recognized as a threat to human health since the time of Hippocrates, ca 400 BC. Successive written accounts of air pollution occur in different countries through the following two millennia until measurements, from the eighteenth century onwards, show the growing scale of poor air quality in urban centres and close to industry, and the chemical characteristics of the gases and particulate matter. The industrial revolution accelerated both the magnitude of emissions of the primary pollutants and the geographical spread of contributing countries as highly polluted cities became the defining issue, culminating with the great smog of London in 1952. Europe and North America dominated emissions and suffered the majority of adverse effects until the latter decades of the twentieth century, by which time the transboundary issues of acid rain, forest decline and ground-level ozone became the main environmental and political air quality issues. As controls on emissions of sulfur and nitrogen oxides (SO2 and NOx) began to take effect in Europe and North America, emissions in East and South Asia grew strongly and dominated global emissions by the early years of the twenty-first century. The effects of air quality on human health had also returned to the top of the priorities by 2000 as new epidemiological evidence emerged. By this time, extensive networks of surface measurements and satellite remote sensing provided global measurements of both primary and secondary pollutants. Global emissions of SO2 and NOx peaked, respectively, in ca 1990 and 2018 and have since declined to 2020 as a result of widespread emission controls. By contrast, with a lack of actions to abate ammonia, global emissions have continued to grow. This article is part of a discussion meeting issue 'Air quality, past present and future'.

Physicalism, realization, and structure.

In the philosophy of mind and psychology, a central question since the 1960s has been that of how to give a philosophically adequate formulation of mind-body physicalism. A large quantity of work on the topic has been done in the interim. There have been, and continue to be, extensive discussions of the ideas of physicalism, identity, functionalism, realization, and constitution. My aim in this paper is a modest one: it is to get clearer about these ideas and some of their interrelations. After providing some background and history, I shall focus on two related topics: the distinction between a functional property and a structural one and the dispute over whether a realization account of the mental-physical relation provides a better physicalist account than a constitutional account.

Associations between environmental factors and hospital admissions for sickle cell disease.

Sickle cell disease is an increasing global health burden. This inherited disease is characterized by a remarkable phenotypic heterogeneity, which can only partly be explained by genetic factors. Environmental factors are likely to play an important role but studies of their impact on disease severity are limited and their results are often inconsistent. This study investigated associations between a range of environmental factors and hospital admissions of young patients with sickle cell disease in London and in Paris between 2008 and 2012. Specific analyses were conducted for subgroups of patients with different genotypes and for the main reasons for admissions. Generalized additive models and distributed lag non-linear models were used to assess the magnitude of the associations and to calculate relative risks. Some environmental factors significantly influence the numbers of hospital admissions of children with sickle cell disease, although the associations identified are complicated. Our study suggests that meteorological factors are more likely to be associated with hospital admissions for sickle cell disease than air pollutants. It confirms previous reports of risks associated with wind speed (risk ratio: 1.06/standard deviation; 95% confidence interval: 1.00-1.12) and also with rainfall (1.06/standard deviation; 95% confidence interval: 1.01-1.12). Maximum atmospheric pressure was found to be a protective factor (0.93/standard deviation; 95% confidence interval: 0.88-0.99). Weak or no associations were found with temperature. Divergent associations were identified for different genotypes or reasons for admissions, which could partly explain the lack of consistency in earlier studies. Advice to patients with sickle cell disease usually includes avoiding a range of environmental conditions that are believed to trigger acute complications, including extreme temperatures and high altitudes. Scientific evidence to support such advice is limited and sometimes confusing. This study shows that environmental factors do explain some of the variations in rates of admission to hospital with acute symptoms in sickle cell disease, but the associations are complex, and likely to be specific to different environments and the individual's exposure to them. Furthermore, this study highlights the need for prospective studies with large numbers of patients and standardized protocols across Europe.

Estimating Particulate Exposure from Modern Municipal Waste Incinerators in Great Britain.

Municipal Waste Incineration (MWI) is regulated through the European Union Directive on Industrial Emissions (IED), but there is ongoing public concern regarding potential hazards to health. Using dispersion modeling, we estimated spatial variability in PM10 concentrations arising from MWIs at postcodes (average 12 households) within 10 km of MWIs in Great Britain (GB) in 2003-2010. We also investigated change points in PM10 emissions in relation to introduction of EU Waste Incineration Directive (EU-WID) (subsequently transposed into IED) and correlations of PM10 with SO2, NOx, heavy metals, polychlorinated dibenzo-p-dioxins/furan (PCDD/F), polycyclic aromatic hydrocarbon (PAH) and polychlorinated biphenyl (PCB) emissions. Yearly average modeled PM10 concentrations were 1.00 × 10-5 to 5.53 × 10-2 µg m-3, a small contribution to ambient background levels which were typically 6.59-2.68 × 101 µg m-3, 3-5 orders of magnitude higher. While low, concentration surfaces are likely to represent a spatial proxy of other relevant pollutants. There were statistically significant correlations between PM10 and heavy metal compounds (other heavy metals (r = 0.43, p = <0.001)), PAHs (r = 0.20, p = 0.050), and PCBs (r = 0.19, p = 0.022). No clear change points were detected following EU-WID implementation, possibly as incinerators were operating to EU-WID standards before the implementation date. Results will be used in an epidemiological analysis examining potential associations between MWIs and health outcomes.

Associations of short-term exposure to traffic-related air pollution with cardiovascular and respiratory hospital admissions in London, UK.

OBJECTIVES: There is evidence of adverse associations between short-term exposure to traffic-related pollution and health, but little is known about the relative contribution of the various sources and particulate constituents. METHODS: For each day for 2011-2012 in London, UK over 100 air pollutant metrics were assembled using monitors, modelling and chemical analyses. We selected a priori metrics indicative of traffic sources: general traffic, petrol exhaust, diesel exhaust and non-exhaust (mineral dust, brake and tyre wear). Using Poisson regression models, controlling for time-varying confounders, we derived effect estimates for cardiovascular and respiratory hospital admissions at prespecified lags and evaluated the sensitivity of estimates to multipollutant modelling and effect modification by season. RESULTS: For single day exposure, we found consistent associations between adult (15-64 years) cardiovascular and paediatric (0-14 years) respiratory admissions with elemental and black carbon (EC/BC), ranging from 0.56% to 1.65% increase per IQR change, and to a lesser degree with carbon monoxide (CO) and aluminium (Al). The average of past 7 days EC/BC exposure was associated with elderly (65+ years) cardiovascular admissions. Indicated associations were higher during the warm period of the year. Although effect estimates were sensitive to the adjustment for other pollutants they remained consistent in direction, indicating independence of associations from different sources, especially between diesel and petrol engines, as well as mineral dust. CONCLUSIONS: Our results suggest that exhaust related pollutants are associated with increased numbers of adult cardiovascular and paediatric respiratory hospitalisations. More extensive monitoring in urban centres is required to further elucidate the associations.

Monitoring air pollution: use of early warning systems for public health.

Research confirming the detrimental impact poor ambient air quality and episodes of abnormally high pollutants has on public health, plus differential susceptibility, calls for improved understanding of this complex topic among all walks of society. The public and particularly, vulnerable groups, should be aware of their quality of air, enabling action to be taken in the event of increased pollution. Policy makers must have a sound awareness of current air quality and future trends, to identify issues, guide policies and monitor their effectiveness. These attitudes are dependent upon air pollution monitoring, forecasting and reporting, serving all interested parties. Apart from the underlying national regulatory obligation a country has in reporting air quality information, data output serves several purposes. This review focuses on provision of real-time data and advanced warnings of potentially health-damaging events, in the form of national air quality indices and proactive alert services. Some of the challenges associated with designing these systems include technical issues associated with the complexity of air pollution and its science. These include inability to provide precise exposure concentrations or guidance on long-term/cumulative exposures or effects from pollutant combinations. Other issues relate to the degree to which people are aware and positively respond to these services. Looking to the future, mobile devices such as cellular phones, equipped with sensing applications have potential to provide dynamic, temporally and spatially precise exposure measures for the mass population. The ultimate aim should be to empower people to modify behaviour-for example, when to increase medication, the route/mode of transport taken to school or work or the appropriate time to pursue outdoor activities-in a way that protects their health as well as the quality of the air they breathe.

Sources of particle number concentration and noise near London Gatwick Airport.

There is increasing evidence of potential health impacts from both aircraft noise and aircraft-associated ultrafine particles (UFP). Measurements of noise and UFP are however scarce near airports and so their variability and relationship are not well understood. Particle number size distributions and noise levels were measured at two locations near Gatwick airport (UK) in 2018-19 with the aim to characterize particle number concentrations (PNC) and link PNC sources, especially UFP, with noise. Positive Matrix Factorization was used on particle number size distribution to identify these sources. Mean PNC (7500-12,000 p cm-3) were similar to those measured close to a highly trafficked road in central London. Peak PNC (94,000 p cm-3) were highest at the site closer to the runway. The airport source factor contributed 17% to the PNC at both sites and the concentrations were greatest when the respective sites were downwind of the runway. However, the main source of PNC was associated with traffic emissions. At both sites noise levels were above the recommendations by the WHO (World Health Organisation). Regression models of identified UFP sources and noise suggested that the largest source of noise (LAeq-1hr) above background was associated with sources of fresh traffic and urban UFP depending on the site. Noise and UFP correlations were moderate to low suggesting that UFP are unlikely to be an important confounder in epidemiological studies of aircraft noise and health. Correlations between UFP and noise were affected by meteorological factors, which need to be considered in studies of short-term associations between aircraft noise and health.

Challenges and policy implications of long-term changes in mass absorption cross-section derived from equivalent black carbon and elemental carbon measurements in London and south-east England in 2014-2019.

Determining the concentration of carbonaceous particles in ambient air is important for climate modelling, source attribution and air quality management. This study presents the difficulties associated with the interpretation of apparent long-term changes in the mass absorption cross section (MAC) of carbonaceous particles in London and south-east England based on equivalent black carbon (eBC) and elemental carbon (EC) measurements between 2014 and 2019. Although these two measurement techniques were used to determine the concentration of carbonaceous aerosols, the concentrations of eBC and EC changed at different rates at all sites, and exhibited different long-term trends. eBC measurements obtained using aethalometer instruments for traffic and urban background sites demonstrated consistent trends, showing decreases in concentrations of up to -12.5% y-1. The EC concentrations showed no change at the urban background location, a similar change to eBC at the traffic site and a significant upward trend of +10% y-1 was observed at the rural site. Despite these differences, the trends in the MAC values decreased at all sites in a similar way, with rates of change from -5.5% y-1 to -10.1% y-1. The different trends and magnitudes of change for the eBC and EC concentrations could lead to uncertainty in quantifying the efficacy of intervention measures and to different conclusions for policy making. This paper provides possible explanations of the observed decrease in MAC values over time.

Urban ambient particle metrics and health: a time-series analysis.

BACKGROUND: Epidemiologic evidence suggests that exposure to ambient particulate matter is associated with adverse health effects. Little is known, however, about which components of the particulate mixture (size, number, source, toxicity) are most relevant to health. We investigated associations of a range of particle metrics with daily deaths and hospital admissions in London. METHODS: Daily concentrations of particle mass (PM10, PM2.5, and PM(10-2.5)), measured using gravimetric, tapered-element-oscillating, and filter-dynamic-measurement-system samplers, as well as particle number concentration and particle composition (carbon, sulfate, nitrate and chloride), were collected from a background monitoring station in central London between 2000 and 2005. All-cause and cause-specific deaths and emergency admissions to hospital in London for the same period were also collected. A Poisson regression time-series model was used in the analysis. RESULTS: The results were not consistent across the various outcomes and lags. Particle number concentration was associated with daily mortality and admissions, particularly for cardiovascular diseases lagged 1-day; increases in particle number concentration (10,166 n/cm3) were associated with 2.2% (95% confidence interval = 0.6% to 3.8%) and 0.6% (-0.4% to 1.7%) increases in cardiovascular deaths and admissions, respectively. Secondary pollutants, especially nonprimary PM2.5, nitrate and sulfate, were more important for respiratory outcomes. CONCLUSIONS: This study provides some evidence that specific components of the particle mixture for air pollutants may be relevant to specific diseases. Interpretation should be cautious, however, in particular because exposures were based upon data from a single centrally located monitoring site. There is a need for replication with more comprehensive exposure data, both in London and elsewhere.

Particulate oxidative burden associated with firework activity.

Firework events are capable of inducing particulate matter (PM) episodes that lead to exceedances of regulatory limit values. As short-term peaks in ambient PM concentration have been associated with negative impacts on respiratory and cardiovascular health, we performed a detailed study of the consequences of firework events in London on ambient air quality and PM composition. These changes were further related to the oxidative activity of daily PM samples by assessing their capacity to drive the oxidation of physiologically important lung antioxidants including ascorbate, glutathione and urate (oxidative potential, OP). Twenty-four hour ambient PM samples were collected at the Marylebone Road sampling site in Central London over a three week period, including two major festivals celebrated with pyrotechnic events: Guy Fawkes Night and Diwali. Pyrotechnic combustion events were characterized by increased gas phase pollutants levels (NO(x) and SO(2)), elevated PM mass concentrations, and trace metal concentrations (specifically Sr, Mg, K, Ba, and Pb). Relationships between NO(x), benzene, and PM(10) were used to apportion firework and traffic source fractions. A positive significant relationship was found between PM oxidative burden and individual trace metals associated with each of these apportioned source fractions. The level of exposure to each source fraction was significantly associated with the total OP. The firework contribution to PM total OP, on a unit mass basis, was greater than that associated with traffic sources: a 1 µg elevation in firework and traffic PM fraction concentration was associated with a 6.5 ± 1.5 OP(T) µg(-1) and 5.2 ± 1.4 OP(T) µg(-1) increase, respectively. In the case of glutathione depletion, firework particulate OP (3.5 ± 0.8 OP(GSH) µg(-1)) considerably exceeded that due to traffic particles (2.2 ± 0.8 OP(GSH) µg(-1)). Therefore, in light of the elevated PM concentrations caused by firework activity and the increased oxidative activity of this PM source, there is value in examining if firework derived PM is related to acute respiratory outcomes.

Development and transferability of ultrafine particle land use regression models in London.

Due to a lack of routine monitoring, bespoke measurements are required to develop ultrafine particle (UFP) land use regression (LUR) models, which is especially challenging in megacities due to their large area. As an alternative, for London, we developed separate models for three urban residential areas, models combining two areas, and models using all three areas. Models were developed against annual mean ultrafine particle count cm-3 estimated from repeated 30-min fixed-site measurements, in different seasons (2016-2018), at forty sites per area, that were subsequently temporally adjusted using continuous measurements from a single reference site within or close to each area. A single model and 10 models were developed for each individual area and combination of areas. Within each area, sites were split into 10 groups using stratified random sampling. Each of the 10 models were developed using 90% of sites. Hold-out validation was performed by pooling the 10% of sites held-out each time. The transferability of models was tested by applying individual and two-area models to external area(s). In model evaluation, within-area mean squared error (MSE) R2 ranged from 14% to 48%. Transferring individual- and combined-area models to external areas without calibration yielded MSE-R2 ranging from -18 to 0. MSE-R2 was in the range 21% to 41% when using particle number count (PNC) measurements in external areas to calibrate models. Our results suggest that the UFP models could be transferred to other areas without calibration in London to assess relative ranking in exposures but not for estimating absolute values of PNC.

Risk of congenital anomalies near municipal waste incinerators in England and Scotland: Retrospective population-based cohort study.

BACKGROUND: Few studies have investigated congenital anomalies in relation to municipal waste incinerators (MWIs) and results are inconclusive. OBJECTIVES: To conduct a national investigation into the risk of congenital anomalies in babies born to mothers living within 10 km of an MWI associated with: i) modelled concentrations of PM10 as a proxy for MWI emissions more generally and; ii) proximity of residential postcode to nearest MWI, in areas in England and Scotland that are covered by a congenital anomaly register. METHODS: Retrospective population-based cohort study within 10 km of 10 MWIs in England and Scotland operating between 2003 and 2010. Exposure was proximity to MWI and log of daily mean modelled ground-level particulate matter ≤10 µm diameter (PM10) concentrations. RESULTS: Analysis included 219,486 births, stillbirths and terminations of pregnancy for fetal anomaly of which 5154 were cases of congenital anomalies. Fully adjusted odds ratio (OR) per doubling in PM10 was: 1·00 (95% CI 0·98-1·02) for all congenital anomalies; 0·99 (0·97-1·01) for all congenital anomalies excluding chromosomal anomalies. For every 1 km closer to an MWI adjusted OR was: 1·02 (1·00-1·04) for all congenital anomalies combined; 1·02 (1·00-1·04) for all congenital anomalies excluding chromosomal anomalies; and, for specific anomaly groups, 1·04 (1·01-1·08) for congenital heart defect sand 1·07 (1·02-1·12) for genital anomalies. DISCUSSION: We found no increased risk of congenital anomalies in relation to modelled PM10 emissions, but there were small excess risks associated with congenital heart defects and genital anomalies in proximity to MWIs. These latter findings may well reflect incomplete control for confounding, but a possible causal effect cannot be excluded.