Measuring prognostic awareness in patients with advanced cancer: a scoping review and interpretive synthesis of the impact of hope.

BACKGROUND: Assessment of prognostic awareness (PA) in patients with advanced cancer is challenging because patient responses often indicate their hopes. The objectives of this scoping review were to summarize studies that measured PA in patients with advanced cancer and to synthesize data about how PA was measured and whether hope was incorporated into the measurement. METHODS: MEDLINE and Embase databases were searched from inception to December 14, 2021. Data regarding the impact of hope on assessment of PA were extracted when studies reported on patients' beliefs about prognosis and patients' beliefs about their doctor's opinion about prognosis. An interpretive synthesis approach was used to analyze the data and to generate a theory regarding the incorporation of hope into the assessment of PA. RESULTS: In total, 52 studies representing 23 766 patients were included. Most were conducted in high-income countries and measured PA based on the goal of treatment (curable vs incurable). Five studies incorporated hope into the assessment of PA and reported that among patients who responded that their treatment goal was a cure, an average of 30% also acknowledged that their doctors were treating them with palliative intent. Interpretive synthesis of the evidence generated a trinary conceptualization of PA patients who are aware and accepting of their prognosis; aware and not accepting; and truly unaware. Each of these groups will benefit from different types of interventions to support their evolving PA. CONCLUSION: The trinary conceptualization of PA may promote understanding of the impact of hope in the assessment of PA and guide future research.

Remobilization of legacy arsenic from sediment in a large subarctic waterbody impacted by gold mining.

Arsenic contamination from mining poses an environmental challenge due to the mobility of this redox-sensitive element. This study evaluated arsenic mobility in sediments of Yellowknife Bay (Canada), a large subarctic water body impacted by gold mining during the 20th century. Short-term measurements of arsenic flux from sediment, arsenic profiling of the water column and sediment porewater, and mass balance modelling were conducted to assess the importance of sediment as an arsenic source. Sediment arsenic fluxes were highly variable throughout Yellowknife Bay and ranged from - 65-1520 µg m-2 day-1. Elevated fluxes measured near the mine site were among the highest published for well-oxygenated lakes. Redox boundaries were typically 2-3 cm below the sediment surface as indicated by porewater profiles of iron, manganese, and arsenic, with arsenic maxima of 65-3220 µg L-1 predominately as arsenite. Sediment arsenic flux was positively related to its solid-phase concentration. Modelling indicated sediment was a principal source of arsenic to the water column. Adsorption and precipitation processes in the oxidizing environment of near-surface sediments did not effectively attenuate arsenic remobilized from contaminated sediments. Internal recycling of legacy arsenic between sediment and surface water will impede a return to background conditions in Yellowknife Bay for decades.

Experimental investigation of short-term warming on arsenic flux from contaminated sediments of two well-oxygenated subarctic lakes.

Legacy arsenic (As) contamination from past mining operations remains an environmental concern in lakes of the Yellowknife area (Northwest Territories, Canada) due to its post-depositional mobility in sediment and potential for continued remobilization to surface waters. Warmer temperatures associated with climate change in this subarctic region may impact As internal loading from lake sediments either by a direct effect on sediment porewater diffusion rate or indirect effects on microbial metabolism and sediment redox conditions. This study assessed the influence of warmer temperatures on As diffusion from contaminated sediment of two lakes with contrasting sediment characteristics using an experimental incubation approach. Sediments from Yellowknife Bay (on Great Slave Lake) contained predominately clay and silt with low organic matter (10%) and high As content (1675 µg/g) while sediments of Lower Martin Lake had high organic matter content (~70%) and approximately half the As (822 µg/g). Duplicate sediment batches from each lake were incubated in a temperature-controlled chamber, and overlying water was kept well-oxygenated while As flux from sediment was measured during four weekly temperature treatments (7°C to 21°C, at ~5°C intervals). During the experiment, As diffused from sediment to overlying water in all cores and temperature treatments, with As fluxes ranging from 48-956 µg/m2/day. Arsenic fluxes were greater from Yellowknife Bay sediments, which had higher solid-phase As concentrations, compared to those of Lower Martin Lake. Short-term warming did not stimulate As flux from duplicate cores of either sediment type, in contrast with reported temperature enhancement in other published studies. We conclude that warmer temperatures were insufficient to strongly enhance sediment As diffusion into overlying oxic waters. These observations are relevant for evaluating climate-warming effects on sediment As mobility in subarctic lakes with little or no thermal stratification and a well-oxygenated water column.

Eutrophication and climatic changes lead to unprecedented cyanobacterial blooms in a Canadian sub-Arctic landscape.

Cyanobacterial blooms have been increasing in frequency and intensity but are often considered an issue restricted to temperate and tropical lakes. Here we report on one of the first occurrences of recurring cyanobacterial (Planktothrix spp.) blooms in a sub-Arctic lake from Yellowknife (Northwest Territories, Canada) and provide a long-term environmental context for the recent blooms using local meteorological data and multi-proxy paleolimnological analyses. Multiple co-occurring regional (gold mining emissions and climatic change) and local (land clearance and urbanization) stressors have impacted Jackfish Lake during the 20th and early-21st centuries, which have led to biological responses across multiple trophic levels. The unprecedented post-2013 cyanobacterial blooms were likely a cumulative response to nutrient enrichment and complex climate-mediated changes to lake thermal properties. A regional analysis of eight lakes around Yellowknife revealed that reduced ice cover duration and longer growing seasons have led to an increase in whole-lake primary production, whilst urban lakes were also fertilized by nutrients from local land-use changes in their catchments. Our findings suggest that anthropogenically nutrient-enriched sub-Arctic lakes, akin to their lower-latitude counterparts, may be vulnerable to cyanobacterial blooms in a warming world.

Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series.

Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 (1) suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the malaria drug discovery portfolio for endemic countries, particularly in areas of high transmission in Africa. We describe a structure-based computationally driven lead optimization program of a pyrrole-based series of DHODH inhibitors, leading to the discovery of two candidates for potential advancement to preclinical development. These compounds have improved physicochemical properties over prior series frontrunners and they show no time-dependent CYP inhibition, characteristic of earlier compounds. Frontrunners have potent antimalarial activity in vitro against blood and liver schizont stages and show good efficacy in Plasmodium falciparum SCID mouse models. They are equally active against P. falciparum and Plasmodium vivax field isolates and are selective for Plasmodium DHODHs versus mammalian enzymes.

Clinical research associates experience with missing patient reported outcomes data in cancer randomized controlled trials.

BACKGROUND: Missing patient reported outcomes data threaten the validity of PRO-specific findings and conclusions from randomized controlled trials by introducing bias due to data missing not at random. Clinical Research Associates are a largely unexplored source for informing understanding of potential causes of missing PRO data. The purpose of this qualitative research was to describe factors that influence missing PRO data, as revealed through the lived experience of CRAs. METHODS: Maximum variation sampling was used to select CRAs having a range of experiences with missing PRO data from academic or nonacademic centers in different geographic locations of Canada. Semistructured interviews were audio-recorded, transcribed verbatim, and analyzed according to descriptive phenomenology. RESULTS: Eleven CRAs were interviewed. Analysis revealed several factors that influence missing PRO data that were organized within themes. PROs for routine clinical care compete with PROs for RCTs. Both the paper and electronic formats have benefits and drawbacks. Missing PRO data are influenced by characteristics of the instruments and of the patients. Assessment of PROs at progression of disease is particularly difficult. Deficiencies in center research infrastructure can contribute. CRAs develop relationships with patients that may help reduce missing PRO data. It is not always possible to provide sufficient time to complete the instrument. There is a need for field guidance and a motivation among CRAs to contribute their knowledge to address issues. CONCLUSION: These results enhance understanding of factors influencing missing PRO data and have important implications for designing operational solutions to improve data quality on cancer RCTs.

Factors predicting missing instruments in three cancer randomized clinical trials.

PURPOSE: Missing patient-reported outcome (PRO) data can seriously threaten the validity of randomized clinical trials (RCTs). Identifying which factors predict missing instruments may help researchers develop strategies to prevent it from happening. This study examined the association of factors with time to the first missing instrument after randomization in three cooperative group RCTs. METHODS: We performed descriptive analyses and Cox proportional hazards regressions for three RCTs selected from the Canadian Cancer Trials Group: MA17 (breast cancer), PR7 (prostate cancer), and LY12 (non-Hodgkin's lymphoma). The outcome was the time from randomization to the first missing instrument. Variables for 15 factors were used as covariates based on availability and previously-reported putative associations with missing PRO data. RESULTS: Nine percent of 1352 subjects on MA17, 37% of 923 subjects on PR7, and 59% of 477 subjects on LY12 had a missing instrument. Twenty-five percent of subjects on MA17 had first missing instrument within 4.6 years. The median time to first missing instrument was: not observed for MA17, 7.3 years for PR7, 0.12 years for LY12. Cox regression revealed statistically significant independent associations with outcome for only five factors: baseline age (PR7) and level of well-being (LY12), and centre level of activity (LY12), presence of post-graduate residency training program (MA17, PR7), and centre geographic location (PR7, LY12). CONCLUSION: Many factors reported to have association with missing instruments do not seem to predict time to the first missing instrument after randomization in RCTs. Context is important in understanding the few that may.

Mineralogical, geospatial, and statistical methods combined to estimate geochemical background of arsenic in soils for an area impacted by legacy mining pollution.

The estimation of geochemical background is complex in areas impacted by point sources of atmospheric emissions due to unknowns about pollutant dispersion, persistence of pollutants on the landscape, and natural concentrations of elements associated with parent material. This study combined mineralogical analysis with conventional statistical and geospatial methods to separate anthropogenically impacted soils from unimpacted soils in the Yellowknife area, Northwest Territories, Canada, a region that was exposed to 60 years of arsenic (As)-rich atmospheric mining emissions (1938-1999) and that hosts natural enrichments of As. High concentrations of As (up to 4700 mg kg-1) were measured in publicly accessible soils near decommissioned roaster stacks in the region and strong relationships between As and distance from the main emission sources persisted in surface soils and soils at depth in the soil profile more than 60 years after the bulk of mining emissions were released. Mineralogical analysis provided unambiguous evidence regarding the source of As minerals and highlighted that most As in surface soils within 15 km of Yellowknife is hosted as anthropogenic arsenic trioxide (As2O3), produced by roaster stack emissions. Statistical protocols for the estimation of geochemical background were applied to an existing database of till geochemistry (N = 1490) after removing samples from mining impacted areas. Results suggested geochemical background for the region is 0.25-15 mg kg-1 As, comparable to global averages, with upper thresholds elevated in volcanic units (30 mg kg-1 As) that often host sulfide mineralization in greenstone belts in the region.

Novel Antimalarial Tetrazoles and Amides Active against the Hemoglobin Degradation Pathway in Plasmodium falciparum.

Malaria control programs continue to be threatened by drug resistance. To identify new antimalarials, we conducted a phenotypic screen and identified a novel tetrazole-based series that shows fast-kill kinetics and a relatively low propensity to develop high-level resistance. Preliminary structure-activity relationships were established including identification of a subseries of related amides with antiplasmodial activity. Assaying parasites with resistance to antimalarials led us to test whether the series had a similar mechanism of action to chloroquine (CQ). Treatment of synchronized Plasmodium falciparum parasites with active analogues revealed a pattern of intracellular inhibition of hemozoin (Hz) formation reminiscent of CQ's action. Drug selections yielded only modest resistance that was associated with amplification of the multidrug resistance gene 1 (pfmdr1). Thus, we have identified a novel chemical series that targets the historically druggable heme polymerization pathway and that can form the basis of future optimization efforts to develop a new malaria treatment.

1-Methyl-1H-pyrazole-5-carboxamide Derivatives Exhibit Unexpected Acute Mammalian Toxicity.

A series of 1-methyl-1H-pyrazole-5-carboxamides were synthesized as potent inhibitors of the parasitic nematode of sheep, Haemonchus contortus. These compounds did not show overt cytotoxicity to a range of mammalian cell lines under standard in vitro culture conditions, had high selectivity indices, and were progressed to an acute toxicity study in a rodent model. Strikingly, acute toxicity was observed in mice. Experiments measuring cellular respiration showed a dose-dependent inhibition of mitochondrial respiration. Under these conditions, potent cytotoxicity was observed for these compounds in rat hepatocytes suggesting that the potent acute mammalian toxicity of this chemotype is most likely associated with respiratory inhibition. In contrast, parasite toxicity was not correlated to acute toxicity or cytotoxicity in respiring cells. This paper highlights the importance of identifying an appropriate in vitro predictor of in vivo toxicity early on in the drug discovery pipeline, in particular assessment for in vitro mitochondrial toxicity.

Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria.

Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (1) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus Plasmodium DHODH and Plasmodium parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from 1 leading to improved species selectivity versus mammalian enzymes and equivalent activity on Plasmodium falciparum and Plasmodium vivax DHODH. The best lead DSM502 (37) showed in vivo efficacy at similar levels of blood exposure to 1, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.

Seasonal variation of arsenic and antimony in surface waters of small subarctic lakes impacted by legacy mining pollution near Yellowknife, NT, Canada.

The seasonal variation in lake water arsenic (As) and antimony (Sb) concentrations was assessed in four small (<1.5km2) subarctic lakes impacted by As and Sb emissions from legacy mining activities near Yellowknife, Northwest Territories, Canada. Substantial variation in As concentrations were measured over the two-year period of study in all but the deepest lake (maximum depth 6.9m), including a four-fold difference in As in the shallowest lake ([As]: 172-846µgL-1; maximum depth 0.8m). Arsenic concentrations were enriched following ice cover development in the three shallowest lakes (50-110%) through a combination of physical and biogeochemical processes. Early winter increases in As were associated with the exclusion of solutes from the developing ice-cover; and large increases in As were measured once oxygen conditions were depleted to the point of anoxia by mid-winter. The onset of anoxic conditions within the water column was associated with large increases in the concentration of redox sensitive elements in lake waters (As, iron [Fe], and manganese [Mn]), suggesting coupling of As mobility with Fe and Mn cycling. In contrast, there was little difference in Sb concentrations under ice suggesting that Sb mobility was controlled by factors other than Fe and Mn associated redox processes. A survey of 30 lakes in the region during fall (open-water) and late-winter (under-ice) revealed large seasonal differences in surface water As were more common in lakes with a maximum depth <4m. This threshold highlights the importance of winter conditions and links between physical lake properties and biogeochemical processes in the chemical recovery of As-impacted subarctic landscapes. The findings indicate annual remobilization of As from contaminated lake sediments may be inhibiting recovery in small shallow lakes that undergo seasonal transitions in redox state.

Novel 1-Methyl-1 H-pyrazole-5-carboxamide Derivatives with Potent Anthelmintic Activity.

A phenotypic screen of two different libraries of small molecules against the motility and development of the parasitic nematode Haemonchus contortus led to the identification of two 1-methyl-1 H-pyrazole-5-carboxamide derivatives. Medicinal chemistry optimization targeted modifications of the left-hand side, middle section, and right-hand side of the hybrid structure of these two hits to elucidate the structure-activity relationship (SAR). Initial SAR around these hits allowed for the iterative and directed assembly of a focused set of 30 analogues of their hybrid structure. Compounds 10, 17, 20, and 22 were identified as the most potent compounds, inhibiting the development of the fourth larval (L4) stage of H. contortus at sub-nanomolar potencies while displaying strong selectivity toward the parasite when tested in vitro against the human MCF10A cell line. In addition, compounds 9 and 27 showed promising activity against a panel of other parasitic nematodes, including hookworms and whipworms.

Controls governing the spatial distribution of sediment arsenic concentrations and solid-phase speciation in a lake impacted by legacy mining pollution.

Forty-seven sediment cores were collected as part of a spatial survey of Long Lake, Yellowknife, NWT, Canada to elucidate the physical and geochemical controls on the distribution of arsenic (As) in sediments impacted by the aerial deposition of arsenic trioxide (As2O3) from ore roasting at legacy gold mines. High-resolution profiles of dissolved As in bottom water and porewater were also collected to determine As remobilization and diffusion rates across the sediment-water interface. Arsenic concentrations in Long Lake sediments ranged from 2.2 to 3420 mg kg-1 (dry weight). Two distinct types of sediment As concentration profiles were identified and are interpreted to represent erosional and depositional areas. Water depth is the best predictor of As concentration in the top 5 cm of sediments due to the inferred focusing of fine-grained As2O3 into deeper water. At greater sediment depths, iron (Fe) concentration, as a likely indicator of As, Fe, and sulphur (S) co-diagenesis, was the best predictor of As concentration. The sediments are a source of dissolved As to surface waters through diffusion-controlled release to bottom water. Arsenic concentrations, solid-phase speciation, and diffusive efflux varied laterally across the lake bottom and with sediment depth due to the interplay between sediment-focusing processes and redox reactions, which has implications for human health and ecological risk assessments.

Structure-Activity Relationship Studies of Tolfenpyrad Reveal Subnanomolar Inhibitors of Haemonchus contortus Development.

Recently, we have discovered that the registered pesticide, tolfenpyrad, unexpectedly and potently inhibits the development of the L4 larval stage of the parasitic nematode Haemonchus contortus with an IC50 value of 0.03 µM while displaying good selectivity, with an IC50 of 37.9 µM for cytotoxicity. As a promising molecular template for medicinal chemistry optimization, we undertook anthelmintic structure-activity relationships for this chemical. Modifications of the left-hand side (LHS), right-hand side (RHS), and middle section of the scaffold were explored to produce a set of 57 analogues. Analogues 25, 29, and 33 were shown to be the most potent compounds of the series, with IC50 values at a subnanomolar level of potency against the chemotherapeutically relevant fourth larval (L4) stage of H. contortus. Selected compounds from the series also showed promising activity against a panel of other different parasitic nematodes, such as hookworms and whipworms.

Optimization of Novel 1-Methyl-1 H-Pyrazole-5-carboxamides Leads to High Potency Larval Development Inhibitors of the Barber's Pole Worm.

A phenotypic screen of a diverse library of small molecules for inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of a 1-methyl-1 H-pyrazole-5-carboxamide derivative with an IC50 of 0.29 µM. Medicinal chemistry optimization targeted modifications on the left-hand side (LHS), middle section, and right-hand side (RHS) of the scaffold in order to elucidate the structure-activity relationship (SAR). Strong SAR allowed for the iterative and directed assembly of a focus set of 64 analogues, from which compound 60 was identified as the most potent compound, inhibiting the development of the fourth larval (L4) stage with an IC50 of 0.01 µM. In contrast, only 18% inhibition of the mammary epithelial cell line MCF10A viability was observed, even at concentrations as high as 50 µM.

Isoxazolopyrimidine-Based Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Antimalarial Activity.

Malaria kills nearly 0.5 million people yearly and impacts the lives of those living in over 90 countries where it is endemic. The current treatment programs are threatened by increasing drug resistance. Dihydroorotate dehydrogenase (DHODH) is now clinically validated as a target for antimalarial drug discovery as a triazolopyrimidine class inhibitor (DSM265) is currently undergoing clinical development. We discovered a related isoxazolopyrimidine series in a phenotypic screen, later determining that it targeted DHODH. To determine if the isoxazolopyrimidines could yield a drug candidate, we initiated hit-to-lead medicinal chemistry. Several potent analogues were identified, including a compound that showed in vivo antimalarial activity. The isoxazolopyrimidines were more rapidly metabolized than their triazolopyrimidine counterparts, and the pharmacokinetic data were not consistent with the goal of a single-dose treatment for malaria.

A systematic review and development of a classification framework for factors associated with missing patient-reported outcome data.

BACKGROUND/AIMS: Missing patient-reported outcome data can lead to biased results, to loss of power to detect between-treatment differences, and to research waste. Awareness of factors may help researchers reduce missing patient-reported outcome data through study design and trial processes. The aim was to construct a Classification Framework of factors associated with missing patient-reported outcome data in the context of comparative studies. The first step in this process was informed by a systematic review. METHODS: Two databases (MEDLINE and CINAHL) were searched from inception to March 2015 for English articles. Inclusion criteria were (a) relevant to patient-reported outcomes, (b) discussed missing data or compliance in prospective medical studies, and (c) examined predictors or causes of missing data, including reasons identified in actual trial datasets and reported on cover sheets. Two reviewers independently screened titles and abstracts. Discrepancies were discussed with the research team prior to finalizing the list of eligible papers. In completing the systematic review, four particular challenges to synthesizing the extracted information were identified. To address these challenges, operational principles were established by consensus to guide the development of the Classification Framework. RESULTS: A total of 6027 records were screened. In all, 100 papers were eligible and included in the review. Of these, 57% focused on cancer, 23% did not specify disease, and 20% reported for patients with a variety of non-cancer conditions. In total, 40% of the papers offered a descriptive analysis of possible factors associated with missing data, but some papers used other methods. In total, 663 excerpts of text (units), each describing a factor associated with missing patient-reported outcome data, were extracted verbatim. Redundant units were identified and sequestered. Similar units were grouped, and an iterative process of consensus among the investigators was used to reduce these units to a list of factors that met the guiding principles. The list was organized on a framework, using an iterative consensus-based process. The resultant Classification Framework is a summary of the factors associated with missing patient-reported outcome data described in the literature. It consists of 5 components (instrument, participant, centre, staff, and study) and 46 categories, each with one or more sub-categories or examples. CONCLUSION: A systematic review of the literature revealed 46 unique categories of factors associated with missing patient-reported outcome data, organized into 5 main component groups. The Classification Framework may assist researchers to improve the design of new randomized clinical trials and to implement procedures to reduce missing patient-reported outcome data. Further research using the Classification Framework to inform quantitative analyses of missing patient-reported outcome data in existing clinical trials and to inform qualitative inquiry of research staff is planned.

Arsenic mobility and characterization in lakes impacted by gold ore roasting, Yellowknife, NWT, Canada.

The controls on the mobility and fate of arsenic in lakes impacted by historical gold ore roasting in northern Canada have been examined. A detailed characterization of arsenic solid and aqueous phases in lake waters, lake sediments and sediment porewaters as well as surrounding soils was conducted in three small lakes (<200ha) downwind and within 5 km of the historic mining and roasting operations of Giant Mine (Northwest Territories). These lakes are marked by differing limnological characteristics such as area, depth and organic content. Radiometric age-dating shows that the occurrence of arsenic trioxide in lake sediments coincides with the regional onset of roasting activities. Quantification by advanced electron microscopy shows that arsenic trioxide accounts for up to 6 wt% of the total arsenic in sediments. The bulk (>80 wt%) of arsenic is contained in the form of secondary sulphide precipitates, with iron oxy-hydroxides hosting a minimal amount of arsenic (<1 wt%). Soluble arsenic trioxide particles act as the primary source of arsenic into sediment porewaters. Dissolved arsenic in reducing porewaters both precipitates in-situ as secondary sulphides, and diffuses upwards into the overlying lake waters. Geogenic arsenic phases are present in sediments in low concentrations and are not considered a significant source of arsenic to porewaters or lake waters. Sediment-water interface diffusive flux calculations suggest that the diffusion of dissolved arsenic from porewaters, combined with lake water residence time, are the predominant mechanisms controlling arsenic concentrations in lake waters.

Comparative histories of polycyclic aromatic compound accumulation in lake sediments near petroleum operations in western Canada.

We examined the historical deposition of polycyclic aromatic compounds (PACs) recorded in radiometrically-dated lake sediment cores from a small, conventional oil and gas operation in the southern Northwest Territories (Cameron Hills), and placed these results in the context of previously published work from three other important regions of western Canada: (1) the Athabasca oil sands region in Alberta; (2) Cold Lake, Alberta; and (3) the Mackenzie Delta, NT. Sediment PAC records from the Cameron Hills showed no clear changes in either source or concentrations coincident with the timing of development in these regions. Changes were small in comparison to the clear increases in both parent and alkyl-substituted PACs in response to industrial development from the Athabasca region surface mining of oil sands, where parent PAC diagnostic ratios indicated a shift from pyrogenic sources (primarily wood and coal burning) in pre-development sediments to more petrogenically-sourced PACs in modern sediments. Cores near in-situ oil sand extraction operations showed only modest increases in PAC deposition. This work directly compares the history and trajectory of contamination in lake ecosystems in areas of western Canada impacted by the most common types of hydrocarbon extraction activities, and provides a context for assessing the environmental impacts of oil and gas development in the future.