Considerations when planning and conducting large global observational studies: Experience from the DISCOVER study of patients with type 2 diabetes.

DISCOVER is a global programme of observational research that includes patients with type 2 diabetes initiating second-line glucose-lowering therapy from 38 countries worldwide, including many with little or no previous epidemiological data available. More than 15,000 patients were followed-up for 3 years, and comprehensive data were collected using a standardized electronic case report form at enrolment, and 6, 12, 24 and 36 months. The study has formed the basis for a long-term registry that is intended to expand the geographic and clinical scope of the study and allow data collection beyond 3 years. In this review, critical aspects of study planning and implementation are summarized, along with challenges that were faced, to provide a resource for researchers planning similar studies. In particular, it is essential to set realistic expectations regarding the degree of study representativeness that can be achieved, allow for sufficient time to obtain ethics committee approval, develop tools to help recruit patients effectively, ensure that data collection systems are robust, user-friendly and adaptable, plan adequate remote and on-site monitoring, maximize patient retention through continuous engagement with study sites and ensure that everyone involved in the study forms a friendly and effective team. Observational studies such as DISCOVER are crucial for understanding disease epidemiology and management in real-world settings. They are also increasingly used by governmental, regulatory and payor agencies for post-marketing surveillance and when considering new drug submissions. The development of future studies of similar scope and ambition to DISCOVER is encouraged.

Using epibenthic fauna as biomonitors of local marine contamination adjacent to McMurdo Station, Antarctica.

Ten benthic fauna taxa in a polluted marine area adjacent to McMurdo Station, Antarctica were deemed to be potential biomonitors because PCBs, DDTs, PAHs, copper, lead and/or zinc in their tissues were significantly higher than in tissues of taxa living in reference areas (p < 0.05). Concentrations of PCBs and DDT were highest in Trematomus (fish). Total PAH concentrations were highest in Alcyonium antarcticum (soft coral), Isotealia antarctica (anemone) and L. elliptica. Copper and lead concentrations were highest in Laternula elliptica (bivalve) and Flabegraviera mundata (polychaete), and lowest in Trematomus and Parbolasia corrugatus (nemertean). However, copper concentrations were even higher in the asteroids Perknaster fuscus antarcticus, Odontaster validus and Psilaster charcoti. Bioaccumulation factors for different species were highest for PCBs and DDT, and lowest for lead. Bioaccumulation of some contaminants are likely prevalent in benthic taxa at McMurdo Station, but concentrations are usually low relative to human consumption standards.

Maternal exposure to polycyclic aromatic hydrocarbons in South Texas, evaluation of silicone wristbands as personal passive samplers.

BACKGROUND: Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with adverse health effects in children. Valid exposure assessment methods with accurate spatial and temporal resolution across pregnancy is a critical need for advancing environmental health studies. OBJECTIVE: The objective of this study was to quantify maternal PAH exposure in pregnant women residing in McAllen, Texas where the prematurity rate and childhood asthma prevalence rates are high. A secondary objective was to compare PAH levels in silicone wristbands deployed as passive samplers with concentrations measured using standardized active air-sampling techniques. METHODS: Participants carried a backpack that contained air-sampling equipment (i.e., filter and XAD sorbent) and a silicone wristband (i.e., passive sampler) for three nonconsecutive 24-h periods. Filters, XAD tubes, and wristbands were analyzed for PAHs. RESULTS: The median level of exposure for the sum of 16 PAHs measured via active sampling over 24 h was 5.54 ng/m3 (filters) and 43.82 ng/m3 (XADs). The median level measured in wristbands (WB) was 586.82 ng/band. Concentrations of the PAH compounds varied across sampling matrix type. Phenanthrene and fluorene were consistently measured for all participants and in all matrix types. Eight additional volatile PAHs were measured in XADs and WBs; the median level of exposure for the sum of these eight PAHs was 342.98 ng/m3 (XADs) and 632.27 ng/band. The silicone wristbands (WB) and XAD sorbents bound 1-methynaphthalyne, 2-methylnaphthalene, biphenyl following similar patterns of detection. SIGNIFICANCE: Since prior studies indicate linkages between PAH exposure and adverse health outcomes in children at the PAH levels detected in our study, further investigation on the associated health effects is needed. Data reflect the ability of silicone wristbands to bind smaller molecular weight, semivolatile PAHs similar to XAD resin. Application of wristbands as passive samplers may be useful in studies evaluating semivolatile PAHs.

Long-term changes in contamination and macrobenthic communities adjacent to McMurdo Station, Antarctica.

Improved waste management at McMurdo Station, Antarctica beginning in the 1980s has been followed by decreases in polycyclic aromatic hydrocarbon (PAH) and metal contamination in the adjacent marine sediments. However, determining the effect of the decreased contamination on marine ecological indicators (macrobenthic fauna) is confounded by concurrent changes in climate cycles and other physical forces. Between 2000 and 2013, there was a decrease in concentrations of some contaminants including mercury, copper, organochlorines, and PAHs in marine sediments adjacent to McMurdo Station. PAH concentrations in Winter Quarters Bay decreased an order of magnitude from 2000/2003 to 2012/2013 and were within an order of magnitude of reference area concentrations by 2013. Macrobenthic communities did not indicate any sign of recovery and have not become more similar to reference communities over this same period of time. Temporal changes in macrobenthic community composition during the study period had higher correlations with climatic and sea ice dynamics than with changes in contaminant concentrations. The Interdecadal Pacific Oscillation climatic index had the highest correlation with macrobenthic community composition. The Antarctic Oscillation climatic index, maximum ice extent and other natural environmental factors also appear to influence macrobenthic community composition. Despite large improvements in environmental management at McMurdo Station, continuing environmental vigilance is necessary before any noticeable improvement in ecological systems is likely to occur. The effects of climate must be considered when determining temporal changes in anthropogenic effects in Antarctica. Maintaining long-term monitoring of both contaminants and ecological indicators is important for determining the localized and global influences of humans on Antarctica, which will have implications for the whole planet.

Measured and predicted acute toxicity of phenanthrene and MC252 crude oil to vertically migrating deep-sea crustaceans.

Deep-water column micronekton play a key role in oceanic food webs and represent an important trophic link between deep- and shallow-water ecosystems. Thus, the potential impacts of sub-surface hydrocarbon plumes on these organisms are critical to developing a more complete understanding of ocean-wide effects resulting from deep-sea oil spills. This work was designed to advance the understanding of hydrocarbon toxicity in several ecologically important deep-sea micronekton species using controlled laboratory exposures aimed at determining lethal threshold exposure levels. The current study confirmed the results previously determined for five deep-sea micronekton by measuring lethal threshold levels for phenanthrene between 81.2 and 277.5 µg/L. These results were used to calibrate the target lipid model and to calculate a critical target lipid body burden for each species. In addition, an oil solubility model was used to predict the acute toxicity of MC252 crude oil to vertically migrating crustaceans, Janicella spinacauda and Euphausiidae spp., and to compare the predictions with results of a 48-h constant exposure toxicity test with passive-dosing. Results confirmed that the tested deep-sea micronekton appear more sensitive than many other organisms when exposed to dissolved oil, but baseline stress complicated interpretation of results.

Mesocosm experiments to better understand hydrocarbon half-lives for oil and oil dispersant mixtures.

Concerns on the timing and processes associated with petroleum degradation were raised after the use of Corexit during the Deepwater Horizon oil spill. There is a lack of understanding of the removal of oil associated with flocculate materials to the sediment. Mesocosm studies employing coastal and open-ocean seawater from the Gulf of Mexico were undertaken to examine changes in oil concentration and composition with time. The water accommodated fractions (WAF) and chemically enhanced WAF (CEWAF) produced using Macondo surrogate oil and Corexit were followed over 3-4 days in controlled environmental conditions. Environmental half-lives of estimated oil equivalents (EOE), polycyclic aromatic hydrocarbons (PAH), n-alkanes (C10-C35), isoprenoids pristane and phytane, and total petroleum hydrocarbons (TPH) were determined. EOE and PAH concentrations decreased exponentially following first-order decay rate kinetics. WAF, CEWAF and DCEWAF (a 10X CEWAF dilution) treatments half-lives ranged from 0.9 to 3.2 days for EOE and 0.5 to 3.3 days for PAH, agreeing with estimates from previous mesocosm and field studies. The aliphatic half-lives for CEWAF and DECWAF treatments ranged from 0.8 to 2.0 days, but no half-life for WAF could be calculated as concentrations were below the detection limits. Biodegradation occurred in all treatments based on the temporal decrease of the nC17/pristane and nC18/phytane ratios. The heterogeneity observed in all treatments was likely due to the hydrophobicity of oil and weathering processes occurring at different rates and times. The presence of dispersant did not dramatically change the half-lives of oil. Comparing degradation of oil alone as well as with dispersant present is critical to determine the fate and transport of these materials in the ocean.

Systematic Literature Review of Systemic Corticosteroid Use for Asthma Management.

Systemic corticosteroid use to manage uncontrolled asthma and its associated healthcare burden may account for important health-related adverse effects. We conducted a systematic literature review to investigate the real-world extent and burden of systemic corticosteroid use in asthma. We searched MEDLINE and Embase databases to identify English-language articles published in 2010-2017, using search terms for asthma with keywords for oral corticosteroids and systemic corticosteroids. Observational studies, prescription database analyses, economic analyses, and surveys on oral/systemic corticosteroid use in children (>5 yr old), adolescents (12-17 yr old), and adults with asthma were included. We identified and reviewed 387 full-text articles, and our review included data from 139 studies. The included studies were conducted in Europe, North America, and Asia. Overall, oral/systemic corticosteroids were commonly used for asthma management and were more frequently used in patients with severe asthma than in those with milder disease. Long-term oral/systemic corticosteroid use was, in general, less frequent than short-term use. Compared with no use, long-term and repeated short-term oral/systemic corticosteroid use were associated with an increased risk of acute and chronic adverse events, even when doses were comparatively low. Greater oral/systemic corticosteroid exposure was also associated with increased costs and healthcare resource use. This review provides a comprehensive overview of oral/systemic corticosteroid use and associated adverse events for patients with all degrees of asthma severity and exposure duration. We report that oral/systemic corticosteroid use is prevalent in asthma management, and the risks of acute and chronic complications increase with the cumulative oral corticosteroid dosage.

Pazopanib or methotrexate-vinblastine combination chemotherapy in adult patients with progressive desmoid tumours (DESMOPAZ): a non-comparative, randomised, open-label, multicentre, phase 2 study.

BACKGROUND: Desmoid tumours are locally aggressive tumours associated with substantial morbidity. No systemic treatments are approved for this disease, with methotrexate-vinblastine the only chemotherapy regimen assessed in a clinical trial setting to date. VEGF overexpression is a common feature in aggressive desmoid tumours. Pazopanib is an oral antiangiogenic agent targeting VEGF receptors 1, 2, and 3, platelet-derived growth factor receptor-like protein (PDGFR) α and ß, and c-KIT tyrosine kinases. We aimed to assess antitumour activity and safety of targeted therapy or combination chemotherapy in progressive desmoid tumours. METHODS: DESMOPAZ was a non-comparative, randomised, open-label, phase 2 trial conducted at 12 centres from the French Sarcoma Group. We enrolled adults (≥18 years) with progressive desmoid tumours, normal organ function and centrally documented progressive disease according to Response Evaluation Criteria in Solid Tumors version 1.1 based on two imaging assessments obtained within less than a 6-month interval. Participants were randomly assigned (2:1) to oral pazopanib 800 mg per day for up to 1 year or to an intravenous regimen combining vinblastine (5 mg/m2 per dose) and methotrexate (30 mg/m2 per dose), administered weekly for 6 months and then every other week for 6 months. Randomisation was stratified according to inclusion centre and tumour location. The primary endpoint was the proportion of patients who had not progressed at 6 months in the first 43 patients who had received one complete or two incomplete cycles of pazopanib. This endpoint was also assessed as a prespecified exploratory endpoint in all patients who had received one complete or two incomplete cycles of methotrexate-vinblastane. Safety analyses were done for all patients who received at least one dose of allocated treatment. This trial was registered with ClinicalTrials.gov, number NCT01876082. FINDINGS: From Dec 4, 2012, to Aug 18, 2017, 72 patients were enrolled and randomly assigned (n=48 in the pazopanib group; n=24 in the methotrexate-vinblastine group). Median follow-up was 23·4 months (IQR 17·1-25·5). 46 patients in the pazopanib group and 20 patients in the methotrexate-vinblastine group were assessable for activity. In the first 43 patients assessable for the primary endpoint in the pazopanib group, the proportion of patients who had not progressed at 6 months was 83·7% (95% CI 69·3-93·2). The proportion of patients treated with methotrexate-vinblastine who had not progressed at 6 months was 45·0% (95% CI 23·1-68·5). The most common grade 3 or 4 adverse events in the pazopanib group were hypertension (n=10, 21%) and diarrhoea (n=7, 15%) and in the methotrexate-vinblastine group were neutropenia (n=10, 45%) and liver transaminitis (n=4, 18%). 11 patients (23%) had at least one serious adverse event related to study treatment in the pazopanib group, as did and six patients (27%) in the methotrexate-vinblastine group. INTERPRETATION: Pazopanib has clinical activity in patients with progressive desmoid tumours and could be a valid treatment option in this rare and disabling disease. FUNDING: GlaxoSmithKline and Novartis.

Spatial distribution and ecological risk assessment of trace metals in surface sediments of Lake Qaroun, Egypt.

A suite of trace metals was determined in twenty surface sediments collected from Lake Qaroun, which is designated as a natural reserve in 1989 to examine their spatial distribution and their potential environmental impact on the lake. Contamination factor (Cf), enrichment factor (EF), geoaccumulation index (Igeo), and pollution load index (PLI) are applied to evaluate the quality of the lake. The highest concentrations were detected in the eastern portion of the lake near Al-Bats drain. The levels of Ba exceeded the toxicity reference value (TRV) (20 ng/g dw) set by US EPA for all sediments, while sediments collected from Al-Bats region exceeded the TRV for Zn (68 ng/g dw). Arsenic, Ba, Sn, Co, Cu, and Hg are poorly correlated with background value of Fe suggesting anthropogenic activities over the entire lake. The values of Cf and Igeo confirmed that the eastern portion of the lake has been found moderately to considerably contaminated by As, Sn, and Zn. Sediments collected from the eastern location (S1) were very highly enriched of Sn (22.47); however, the other eastern locations were highly enriched of Sn, As, Cd, Co, and Ba. It is clear that sites near Al-Bats and El-Wadi drains are hot spots, which got immense amounts of domestic, agricultural, and industrial wastes. Behind the influence of these discharges, concentrations are decreased. The PLI over the entire lake ranged from 0.247 to 0.801 for all sites, which reflect unpolluted status.

Assessment and ecological indicators of total and polycyclic aromatic hydrocarbons in the aquatic environment of lake Manzala, Egypt.

The study objective was to assess the profile of aliphatic and polycyclic aromatic hydrocarbons in the aquatic environment of Lake Manzala and to determine the potential sources and effects of these hydrocarbons. To reach these objectives 24 surface sediment and 24 tilapia fish were collected and analyzed using GC-FID and GC-MS. The highest concentrations for n-alkanes (∑n-C15-35) (19,625 ng g-1) and PAHs (∑45PAHs) (5,153 ng g-1) were found in sediments collected from Bahr Al-Baqar drain while Al-Temsah and Al-Hamra sites contained the lowest concentrations. Different diagnostic molecular ratios for hydrocarbons were used to evaluate sources of the hydrocarbons. The hydrocarbons were found to have differing proportions of petrogenic, pyrogenic, and biogenic sources. Comparison to sediment quality guidelines indicated PAHs were below the effect range low (ERL) with the exception of acenaphthene, fluorine, and ∑45PAHs in Bahr Al-Baqar drain sediments. Tissue samples had moderate PAH concentrations for ∑45PAHs ranging from 302.5 ng g-1 West of Bashteer (S3) to 596 ng g-1 in Legam (S5). Since fish metabolize PAH quickly, their detection suggest continual or very recent exposure. The PAH in sediment and fish from Lake Manzala are at a low or below level of environmental concern.

Larval digestion of different manure types by the black soldier fly (Diptera: Stratiomyidae) impacts associated volatile emissions.

Volatile emissions from decomposing animal waste are known environmental pollutants. The black soldier fly, Hermetia illucens (L.), is being evaluated for industrialization as a means to recycle wastes and produce protein for use as food and feed. We examined the ability of black soldier fly larvae to reduce odorous compounds associated with animal wastes. Black soldier fly larvae were reared under laboratory conditions on poultry, swine, and dairy manure at feed rates of 18.0 and 27.0 g every other day until 40% reached the prepupal stage. Volatile emissions were collected and analyzed from freshly thawed as well as the digested waste when 90% of the black soldier fly larvae reached the prepupal stage. Volatiles were also collected simultaneously from manure not inoculated with black soldier fly larvae (non-digested) and held under similar conditions. Manure samples were analyzed for relative amounts of nine select odorous volatile organic compounds: phenol, 4-methylphenol, indole, 3-methylindole, propanoic acid, 2-methylpropanoic acid, butanoic acid, 3-methylbutanoic acid and pentanoic acid. Black soldier fly larvae reduced emissions of all volatile organic compounds by 87% or greater. Complete reductions were observed for 2-methly propanoic acid in digested poultry manure, phenol, 4-methylphenol, indole and all five fatty acids in digested swine manure, and 4-methylphenol, indole, 3-methylindole and all five acids in digested dairy manure. This study is the first to identify volatile emissions from manure digested by black soldier fly larvae and compare to those found in non-digested manure. These data demonstrate additional benefits of using black soldier fly larvae as a cost-effective and environmentally friendly means of livestock manure management in comparison to current methods. CAPSULE: Black soldier fly larvae are capable of altering the overall profile of volatile organic compounds and reducing levels of targeted odorous compounds in livestock manure.

A method for the production of large volumes of WAF and CEWAF for dosing mesocosms to understand marine oil snow formation.

Marine oil snow (MOS) formation is a mechanism to transport oil from the ocean surface to sediments. We describe here the use of 110L mesocosms designed to mimic oceanic parameters during an oil spill including the use of chemical dispersants in order to understand the processes controlling MOS formation. These experiments were not designed to be toxicity tests but rather to illustrate mechanisms. This paper focuses on the development of protocols needed to conduct experiments under environmentally relevant conditions to examine marine snow and MOS. The experiments required the production of over 500 liters of water accommodated fraction (WAF), chemically enhanced water accommodated fraction of oil (CEWAF) as well as diluted CEWAF (DCEWAF). A redesigned baffled (170 L) recirculating tank (BRT) system was used. Two mesocosm experiments (M1 and M2) were run for several days each. In both M1 and M2, marine snow and MOS was formed in controls and all treatments respectively. Estimated oil equivalent (EOE) concentrations of CEWAF were in the high range of concentrations reported during spills and field tests, while WAF and DCEWAF concentrations were within the range of concentrations reported during oil spills. EOE decreased rapidly within days in agreement with historic data and experiments.

Characterization of Variability in Toxicokinetics and Toxicodynamics of Tetrachloroethylene Using the Collaborative Cross Mouse Population.

BACKGROUND: Evaluation of interindividual variability is a challenging step in risk assessment. For most environmental pollutants, including perchloroethylene (PERC), experimental data are lacking, resulting in default assumptions being used to account for variability in toxicokinetics and toxicodynamics. OBJECTIVE: We quantitatively examined the relationship between PERC toxicokinetics and toxicodynamics at the population level to test whether individuals with increased oxidative metabolism are be more sensitive to hepatotoxicity following PERC exposure. METHODS: Male mice from 45 strains of the Collaborative Cross (CC) were orally administered a single dose of PERC (1,000 mg/kg) or vehicle (Alkamuls-EL620) and euthanized at various time points (n = 1/strain/time). Concentration­time profiles were generated for PERC and its primary oxidative metabolite trichloroacetate (TCA) in multiple tissues. Toxicodynamic phenotyping was also performed. RESULTS: Significant variability among strains was observed in toxicokinetics of PERC and TCA in every tissue examined. Based on area under the curve (AUC), the range of liver TCA levels spanned nearly an order of magnitude (~8-fold). Expression of liver cytochrome P4502E1 did not correlate with TCA levels. Toxicodynamic phenotyping revealed an effect of PERC on bodyweight loss, induction of peroxisome proliferator activated receptor-alpha (PPARα)-regulated genes, and dysregulation of hepatic lipid homeostasis. Clustering was observed among a) liver levels of PERC, TCA, and triglycerides; b) TCA levels in liver and kidney; and c) TCA levels in serum, brain, fat, and lung. CONCLUSIONS: Using the CC mouse population model, we have demonstrated a complex and highly variable relationship between PERC and TCA toxicokinetics and toxicodynamics at the population level. https://doi.org/10.1289/EHP788.

Distribution and residue profile of organochlorine pesticides and polychlorinated biphenyls in sediment and fish of Lake Manzala, Egypt.

Sediment and fish (Oreochromis niloticus) samples collected from Lake Manzala were analyzed to assess the spatial distribution of OCPs and 96 PCBs. Relatively higher concentrations of chlorpyrifos, ∑DDT, and HCB were found, particularly at the Bahr Al-Baqar drain station, which has uncontrolled inputs of untreated domestic, agricultural, and industrial wastes. The concentrations of ∑PCBs ranged from 19 to 69 ng/g dw and from 7.4 to 29 ng/g dw for sediment and fish samples, respectively. Ratios of DDT to its metabolites suggest that the source of ∑DDT is from past usage of technical DDT in the regions surrounding the lake. Sediment quality guidelines were exceeded in 88, 75, and 42% of sediments for the Effects Range Low (ERL) for ∑PCBs, ∑DDT, and 4,4'-DDE, respectively. Sediment from the Bahr Al-Baqar drain exceeded the Probable Effects Level (PEL) for DDT isomers 2,4' and 4,4'. All fish samples from Lake Manzala were well below action and tolerance levels set by US EPA for ∑DDT, chlordane, dieldrin, heptachlor, mirex, and PCBs. HIGHLIGHTS: Distributions of OCPs and PCBs in sediment and tilapia from Lake Manzala were investigated. Chlorpyrifos, ∑DDT, and HCB sediment concentrations were spatially variable and relatively elevated. ∑96PCBs, ∑DDT, and 4,4'-DDE exceeded the Effects Range Low in 88, 75, and 42% of the sediments, respectively. The major input from Cairo, the Bahr Al-Baqar drain, exceeded the Probable Effects Level for DDT isomers in sediments. OCP and PCB concentrations in tilapia were below action and tolerance levels set by the US-EPA.

Spatial and temporal distribution of water column total polycyclic aromatic hydrocarbons (PAH) and total petroleum hydrocarbons (TPH) from the Deepwater Horizon (Macondo) incident.

Pre-spill background concentrations of TPH and PAH in water samples from the Gulf of Mexico are compared with samples (over 20,000) collected during and after the Deepwater Horizon incident (13,000 stations). Samples were collected by multiple response agencies, trustees and BP and reported in the Gulf Science Data. The samples were collected from a few m to over 800 km in all directions from the wellhead. During the incident, samples with the highest concentrations of hydrocarbons were collected proximal to the wellhead or in samples collected from surface slicks and dispersant use. Of the 13,172 water sample TPH concentrations reported, 84% were below 1 µg/L (background). Of the 16,557 water sample PAH concentrations reported, 79% were below 0.056 µg/L (the median field blank, background). The percentage of samples below background increased rapidly after the well was capped. The spatial and temporal distributions of these hydrocarbon data are presented.

The Contribution of Peroxisome Proliferator-Activated Receptor Alpha to the Relationship Between Toxicokinetics and Toxicodynamics of Trichloroethylene.

Exposure to the ubiquitous environmental contaminant trichloroethylene (TCE) is associated with cancer and non-cancer toxicity in both humans and rodents. Peroxisome proliferator-activated receptor-alpha (PPARα) is thought to be playing a role in liver toxicity in rodents through activation of the receptor by the TCE metabolite trichloroacetic acid (TCA). However, most studies using genetically altered mice have not assessed the potential for PPARα to alter TCE toxicokinetics, which may lead to differences in TCA internal doses and hence confound inferences as to the role of PPARα in TCE toxicity. To address this gap, male and female wild type (129S1/SvImJ), Pparα-null, and humanized PPARα (hPPARα) mice were exposed intragastrically to 400 mg/kg TCE in single-dose (2, 5 and 12 h) and repeat-dose (5 days/week, 4 weeks) studies. Interestingly, following either a single- or repeat-dose exposure to TCE, levels of TCA in liver and kidney were lower in Pparα-null and hPPARα mice as compared with those in wild type mice. Levels of trichloroethanol (TCOH) were similar in all strains. TCE-exposed male mice consistently had higher levels of TCA and TCOH in all tissues compared with females. Additionally, in both single- and repeat-dose studies, a similar degree of induction of PPARα-responsive genes was observed in liver and kidney of hPPARα and wild type mice, despite the difference in hepatic and renal TCA levels. Additional sex- and strain-dependent effects were observed in the liver, including hepatocyte proliferation and oxidative stress, which were not dependent on TCA or TCOH levels. These data demonstrate that PPARα status affects the levels of the putative PPARα agonist TCA following TCE exposure. Therefore, interpretations of studies using Pparα-null and hPPARα mice need to consider the potential contribution of genotype-dependent toxicokinetics to observed differences in toxicity, rather than attributing such differences only to receptor-mediated toxicodynamic effects.

Low rates of both lipid-lowering therapy use and achievement of low-density lipoprotein cholesterol targets in individuals at high-risk for cardiovascular disease across Europe.

AIMS: To analyse the treatment and control of dyslipidaemia in patients at high and very high cardiovascular risk being treated for the primary prevention of cardiovascular disease (CVD) in Europe. METHODS AND RESULTS: Data were assessed from the European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice (EURIKA, ClinicalTrials.gov identifier: NCT00882336), which included a randomly sampled population of primary CVD prevention patients from 12 European countries (n = 7641). Patients' 10-year risk of CVD-related mortality was calculated using the Systematic Coronary Risk Evaluation (SCORE) algorithm, identifying 5019 patients at high cardiovascular risk (SCORE ≥5% and/or receiving lipid-lowering therapy), and 2970 patients at very high cardiovascular risk (SCORE ≥10% or with diabetes mellitus). Among high-risk individuals, 65.3% were receiving lipid-lowering therapy, and 61.3% of treated patients had uncontrolled low-density lipoprotein cholesterol (LDL-C) levels (≥2.5 mmol/L). For very-high-risk patients (uncontrolled LDL-C levels defined as ≥1.8 mmol/L) these figures were 49.5% and 82.9%, respectively. Excess 10-year risk of CVD-related mortality (according to SCORE) attributable to lack of control of dyslipidaemia was estimated to be 0.72% and 1.61% among high-risk and very-high-risk patients, respectively. Among high-risk individuals with uncontrolled LDL-C levels, only 8.7% were receiving a high-intensity statin (atorvastatin ≥40 mg/day or rosuvastatin ≥20 mg/day). Among very-high-risk patients, this figure was 8.4%. CONCLUSIONS: There is a considerable opportunity for improvement in rates of lipid-lowering therapy use and achievement of lipid-level targets in high-risk and very-high-risk patients being treated for primary CVD prevention in Europe.

Reclassification of European patients' cardiovascular risk using the updated Systematic Coronary Risk Evaluation algorithm.

Data from the European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice (EURIKA; ClinicalTrials.gov; NCT00882336) was used to assess the proportions of patients aged 50-65 years free of diabetes and not receiving lipid-lowering therapy (LLT) considered to be at low (<1%), intermediate (1% to <5%) and high (≥5%) 10-year risk of cardiovascular mortality according to the Systematic Coronary Risk Evaluation (SCORE) algorithm and the updated algorithm that considers patients' total cholesterol and high-density lipoprotein cholesterol (HDL-C) levels as independent variables (SCORE-HDL). Of 2321 patients analysed, 19.3%, 60.7% and 20.0% were considered to be at low, intermediate and high cardiovascular risk respectively according to SCORE, and 25.7%, 57.2% and 17.1% respectively according to SCORE-HDL. Thus, there was an overall trend towards reclassification from higher to lower risk categories when SCORE-HDL was compared with SCORE.

Temporal trends and spatial distribution of DDT in bivalves from the coastal marine environments of the continental United States, 1986-2009.

Analysis of DDT isomers and breakdown products, DDD and DDE, in over 3500 bivalve samples collected from more than 300 locations along the continental United States indicates that concentrations are decreasing. Overall average concentrations for the East (45.8±24.6 ng/gdw), Gulf (42.4±21.1 ng/gdw), and West (90.9±43.3ng/gdw) coasts are declining with an environmental half-life between 10 and 14 ears and are predicted to decrease below 10% of today's concentrations by 2050. Geographically, areas with high and low levels are well identified. Bivalves yielding the highest concentrations were collected in areas linked to areas of DDT production or heavy usage. These areas are clustered in the southern California and San Francisco area, on the West coast; Delaware and Hudson/Raritan Estuary, on the East coast; and in Alabama and northwestern Florida, on the Gulf of Mexico. Statistically significant decreasing trends in ΣDDT concentrations are apparent at most of these locations.

Polychlorinated dibenzo-p-dioxins and dibenzofurans detected in bivalve samples from the NOAA National Status and Trends Program.

Bivalve samples from 142 sites were analyzed to determine the concentration and toxicity equivalents (TEQ) of dioxins and furans (D/F) as part of the NOAA National Status and Trends Program. The total concentration of 17 D/F ranged from not detected to 203 pg/g wet weight of tissue. Octachlorinated dibenzo-p-dioxin, OCDD, had a concentration range from not detected to 189 pg/g and a mean concentration of 8.65 pg/g. OCDD was the dominant D/F compound detected and accounted for, on average, over 70% of the total D/F concentration. The TEQ (compared to 2,3,7,8-TCDD) ranged from 0.12 to 7.32 pg TEQ/g. The TEQ for 39% of the bivalves analyzed were below 0.238 pg TEQ/g. TEQ above human consumption advisory concentration of 1.2 pg TEQ/g were found in 9.3% of the samples analyzed. TEQ for D/F indicate very limited human health concerns from consumption of bivalves at most of the locations sampled.